RecQ Family Helicases in Replication Fork Remodeling and Repair: Opening New Avenues towards the Identification of Potential Targets for Cancer Chemotherapy

Chetan    K.   Jain; Swagata      Mukhopadhyay; Agneyo       Ganguly
Abstract

Replication fork reversal and restart has gained immense interest as a central response mechanism to replication stress following DNA damage. Although the exact mechanism of fork reversal has not been elucidated precisely, the involvement of diverse pathways and different factors has been demonstrated, which are central to this phenomenon. RecQ helicases known for their vital role in DNA repair and maintaining genome stability has recently been implicated in the restart of regressed replication forks. Through interaction with vital proteins like Poly (ADP) ribose polymerase 1 (PARP1), these helicases participate in the replication fork reversal and restart phenomenon. Most therapeutic agents used for cancer chemotherapy act by causing DNA damage in replicating cells and subsequent cell death. These DNA damages can be repaired by mechanisms involving fork reversal as the key phenomenon eventually reducing the efficacy of the therapeutic agent. Hence the factors contributing to this repair process can be good selective targets for developing more efficient chemotherapeutic agents. In this review, we have discussed in detail the role of various proteins in replication fork reversal and restart with special emphasis on RecQ helicases. Involvement of other proteins like PARP1, recombinase rad51, SWI/SNF complex has also been discussed. Since RecQ helicases play a central role in the DNA damage response following chemotherapeutic treatment, we propose that targeting these helicases can emerge as an alternative to available intervention strategies. We have also summarized the current research status of available RecQ inhibitors and siRNA based therapeutic approaches that targets RecQ helicases. In summary, our review gives an overview of the DNA damage responses involving replication fork reversal and provides new directions for the development of more efficient and sustainable chemotherapeutic approaches.
Keywords: Replication fork reversal, replication fork restart, RecQ helicases, DNA repair, chemotherapy, PARP1.
Graphical Abstract

[1] 
Dietlein, F.; Thelen, L.; Reinhardt, H.C. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet.,  2014, 30(8), 326-339.
[http://dx.doi.org/10.1016/j.tig.2014.06.003] [PMID:  25017190] 
[2] 
Christmann, M.; Kaina, B. Transcriptional regulation of human DNA repair genes following genotoxic stress: Trigger mechanisms, inducible responses and genotoxic adaptation. Nucleic Acids Res.,  2013, 41(18), 8403-8420.
[http://dx.doi.org/10.1093/nar/gkt635] [PMID:  23892398] 
[3] 
Christmann, M.; Tomicic, M.T.; Roos, W.P.; Kaina, B. Mechanisms of human DNA repair: An update. Toxicology,  2003, 193(1-2), 3-34.
[http://dx.doi.org/10.1016/S0300-483X(03)00287-7] [PMID:  14599765] 
[4] 
Brosh, R.M., Jr DNA helicases involved in DNA repair and their roles in cancer. Nat. Rev. Cancer,  2013, 13(8), 542-558.
[http://dx.doi.org/10.1038/nrc3560] [PMID:  23842644] 
[5] 
Croteau, D.L.; Popuri, V.; Opresko, P.L.; Bohr, V.A. Human RecQ helicases in DNA repair, recombination, and replication. Annu. Rev. Biochem.,  2014, 83, 519-552.
[http://dx.doi.org/10.1146/annurev-biochem-060713-035428] [PMID:  24606147] 
[6] 
Sharma, S.; Doherty, K.M.; Brosh, R.M., Jr Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability. Biochem. J.,  2006, 398(3), 319-337.
[http://dx.doi.org/10.1042/BJ20060450] [PMID:  16925525] 
[7] 
Umate, P.; Tuteja, N.; Tuteja, R. Genome-wide comprehensive analysis of human helicases. Commun. Integr. Biol.,  2011, 4(1), 118-137.
[http://dx.doi.org/10.4161/cib.13844] [PMID:  21509200] 
[8] 
Matsumoto, T. DNA repair aspects for RecQ helicase disorders. In: DNA Repair and Human Diseases; Springer: Boston, 2006; pp. 20-29.
[9] 
Patel, S.S.; Donmez, I. Mechanisms of helicases. J. Biol. Chem.,  2006, 281(27), 18265-18268.
[http://dx.doi.org/10.1074/jbc.R600008200] [PMID:  16670085] 
[10] 
Bohr, V.A. Rising from the RecQ-age: The role of human RecQ helicases in genome maintenance. Trends Biochem. Sci.,  2008, 33(12), 609-620.
[http://dx.doi.org/10.1016/j.tibs.2008.09.003] [PMID:  18926708] 
[11] 
Larsen, N.B.; Hickson, I.D.; Rec, Q. RecQ helicases: Conserved guardians of genomic integrity. Adv. Exp. Med. Biol.,  2013, 767, 161-184.
[http://dx.doi.org/10.1007/978-1-4614-5037-5_8] [PMID:  23161011] 
[12] 
Sharma, S. An appraisal of RECQ1 expression in cancer progression. Front. Genet.,  2014, 5, 426.
[http://dx.doi.org/10.3389/fgene.2014.00426] [PMID:  25538733] 
[13] 
Machwe, A.; Lozada, E.; Wold, M.S.; Li, G.M.; Orren, D.K. Molecular cooperation between the Werner syndrome protein and replication protein A in relation to replication fork blockage. J. Biol. Chem.,  2011, 286(5), 3497-3508.
[http://dx.doi.org/10.1074/jbc.M110.105411] [PMID:  21107010] 
[14] 
Wu, Y. Unwinding and rewinding: Double faces of helicase? J. Nucleic Acids,  2012, 2012 140601
[http://dx.doi.org/10.1155/2012/140601] [PMID:  22888405] 
[15] 
Bennett, R.J.; Keck, J.L. Structure and function of RecQ DNA helicases. Crit. Rev. Biochem. Mol. Biol.,  2004, 39(2), 79-97.
[http://dx.doi.org/10.1080/10409230490460756] [PMID:  15217989] 
[16] 
Van Maldergem, L.; Siitonen, H.A.; Jalkh, N.; Chouery, E.; De Roy, M.; Delague, V.; Muenke, M.; Jabs, E.W.; Cai, J.; Wang, L.L.; Plon, S.E.; Fourneau, C.; Kestilä, M.; Gillerot, Y.; Mégarbané, A.; Verloes, A. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet.,  2006, 43(2), 148-152.
[http://dx.doi.org/10.1136/jmg.2005.031781] [PMID:  15964893] 
[17] 
Carr, A.M.; Lambert, S. Replication stress-induced genome instability: the dark side of replication maintenance by homologous recombination. J. Mol. Biol.,  2013, 425(23), 4733-4744.
[http://dx.doi.org/10.1016/j.jmb.2013.04.023] [PMID:  23643490] 
[18] 
Atkinson, J.; McGlynn, P. Replication fork reversal and the maintenance of genome stability. Nucleic Acids Res.,  2009, 37(11), 3475-3492.
[http://dx.doi.org/10.1093/nar/gkp244] [PMID:  19406929] 
[19] 
Berti, M.; Ray Chaudhuri, A.; Thangavel, S.; Gomathinayagam, S.; Kenig, S.; Vujanovic, M.; Odreman, F.; Glatter, T.; Graziano, S.; Mendoza-Maldonado, R.; Marino, F.; Lucic, B.; Biasin, V.; Gstaiger, M.; Aebersold, R.; Sidorova, J.M.; Monnat, R.J., Jr; Lopes, M.; Vindigni, A. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat. Struct. Mol. Biol.,  2013, 20(3), 347-354.
[http://dx.doi.org/10.1038/nsmb.2501] [PMID:  23396353] 
[20] 
Ray Chaudhuri, A.; Hashimoto, Y.; Herrador, R.; Neelsen, K.J.; Fachinetti, D.; Bermejo, R.; Cocito, A.; Costanzo, V.; Lopes, M. Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat. Struct. Mol. Biol.,  2012, 19(4), 417-423.
[http://dx.doi.org/10.1038/nsmb.2258] [PMID:  22388737] 
[21] 
Berti, M.; Vindigni, A. Replication stress: Getting back on track. Nat. Struct. Mol. Biol.,  2016, 23(2), 103-109.
[http://dx.doi.org/10.1038/nsmb.3163] [PMID:  26840898] 
[22] 
Higgins, N.P.; Kato, K.; Strauss, B. A model for replication repair in mammalian cells. J. Mol. Biol.,  1976, 101(3), 417-425.
[http://dx.doi.org/10.1016/0022-2836(76)90156-X] [PMID:  1255724] 
[23] 
Neelsen, K.J.; Lopes, M. Replication fork reversal in eukaryotes: From dead end to dynamic response. Nat. Rev. Mol. Cell Biol.,  2015, 16(4), 207-220.
[http://dx.doi.org/10.1038/nrm3935] [PMID:  25714681] 
[24] 
Zellweger, R.; Dalcher, D.; Mutreja, K.; Berti, M.; Schmid, J.A.; Herrador, R.; Vindigni, A.; Lopes, M. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J. Cell Biol.,  2015, 208(5), 563-579.
[http://dx.doi.org/10.1083/jcb.201406099] [PMID:  25733714] 
[25] 
Pommier, Y.; Redon, C.; Rao, V.A.; Seiler, J.A.; Sordet, O.; Takemura, H.; Antony, S.; Meng, L.; Liao, Z.; Kohlhagen, G.; Zhang, H.; Kohn, K.W. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat. Res.,  2003, 532(1-2), 173-203.
[http://dx.doi.org/10.1016/j.mrfmmm.2003.08.016] [PMID:  14643436] 
[26] 
Sugimura, K.; Takebayashi, S.; Taguchi, H.; Takeda, S.; Okumura, K. PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J. Cell Biol.,  2008, 183(7), 1203-1212.
[http://dx.doi.org/10.1083/jcb.200806068] [PMID:  19103807] 
[27] 
Pike, A.C.; Shrestha, B.; Popuri, V.; Burgess-Brown, N.; Muzzolini, L.; Costantini, S.; Vindigni, A.; Gileadi, O. Structure of the human RECQ1 helicase reveals a putative strand-separation pin. Proc. Natl. Acad. Sci. USA,  2009, 106(4), 1039-1044.
[http://dx.doi.org/10.1073/pnas.0806908106] [PMID:  19151156] 
[28] 
Kitano, K. Structural mechanisms of human RecQ helicases WRN and BLM. Front. Genet.,  2014, 5, 366.
[http://dx.doi.org/10.3389/fgene.2014.00366] [PMID:  25400656] 
[29] 
Datta, A.; Brosh, R.M., Jr New insights into DNA helicases as druggable targets for cancer therapy. Front. Mol. Biosci.,  2018, 5, 59.
[http://dx.doi.org/10.3389/fmolb.2018.00059] [PMID:  29998112] 
[30] 
Thangavel, S.; Mendoza-Maldonado, R.; Tissino, E.; Sidorova, J.M.; Yin, J.; Wang, W.; Monnat, R.J., Jr; Falaschi, A.; Vindigni, A. Human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Mol. Cell. Biol.,  2010, 30(6), 1382-1396.
[http://dx.doi.org/10.1128/MCB.01290-09] [PMID:  20065033] 
[31] 
Sharma, S.; Sommers, J.A.; Choudhary, S.; Faulkner, J.K.; Cui, S.; Andreoli, L.; Muzzolini, L.; Vindigni, A.; Brosh, R.M., Jr Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. J. Biol. Chem.,  2005, 280(30), 28072-28084.
[http://dx.doi.org/10.1074/jbc.M500264200] [PMID:  15899892] 
[32] 
Parvathaneni, S.; Stortchevoi, A.; Sommers, J.A.; Brosh, R.M., Jr; Sharma, S. Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks. PLoS One,  2013, 8(5) e62481
[http://dx.doi.org/10.1371/journal.pone.0062481] [PMID:  23650516] 
[33] 
Kawabe, T.; Tsuyama, N.; Kitao, S.; Nishikawa, K.; Shimamoto, A.; Shiratori, M.; Matsumoto, T.; Anno, K.; Sato, T.; Mitsui, Y.; Seki, M.; Enomoto, T.; Goto, M.; Ellis, N.A.; Ide, T.; Furuichi, Y.; Sugimoto, M. Differential regulation of human RecQ family helicases in cell transformation and cell cycle. Oncogene,  2000, 19(41), 4764-4772.
[http://dx.doi.org/10.1038/sj.onc.1203841] [PMID:  11032027] 
[34] 
Sharma, S.; Stumpo, D.J.; Balajee, A.S.; Bock, C.B.; Lansdorp, P.M.; Brosh, R.M., Jr; Blackshear, P.J. RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability. Mol. Cell. Biol.,  2007, 27(5), 1784-1794.
[http://dx.doi.org/10.1128/MCB.01620-06] [PMID:  17158923] 
[35] 
Ellis, N.A.; Groden, J.; Ye, T.Z.; Straughen, J.; Lennon, D.J.; Ciocci, S.; Proytcheva, M.; German, J. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell,  1995, 83(4), 655-666.
[http://dx.doi.org/10.1016/0092-8674(95)90105-1] [PMID:  7585968] 
[36] 
Wu, L.; Hickson, I.D. The Bloom’s syndrome helicase suppresses crossing over during homologous recombination. Nature,  2003, 426(6968), 870-874.
[http://dx.doi.org/10.1038/nature02253] [PMID:  14685245] 
[37] 
Newman, J.A.; Savitsky, P.; Allerston, C.K.; Bizard, A.H.; Özer, Ö.; Sarlós, K.; Liu, Y.; Pardon, E.; Steyaert, J.; Hickson, I.D.; Gileadi, O. Crystal structure of the Bloom’s syndrome helicase indicates a role for the HRDC domain in conformational changes. Nucleic Acids Res.,  2015, 43(10), 5221-5235.
[http://dx.doi.org/10.1093/nar/gkv373] [PMID:  25901030] 
[38] 
German, J.; Sanz, M.M.; Ciocci, S.; Ye, T.Z.; Ellis, N.A. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s syndrome registry. Hum. Mutat.,  2007, 28(8), 743-753.
[http://dx.doi.org/10.1002/humu.20501] [PMID:  17407155] 
[39] 
German, J. Bloom’s syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet.,  1997, 93(1), 100-106.
[http://dx.doi.org/10.1016/S0165-4608(96)00336-6] [PMID:  9062585] 
[40] 
de Renty, C.; Ellis, N.A. Bloom’s syndrome: Why not premature aging? A comparison of the BLM and WRN helicases. Ageing Res. Rev.,  2017, 33, 36-51.
[PMID: 27238185] 
[41] 
Bachrati, C.Z.; Borts, R.H.; Hickson, I.D. Mobile D-loops are a preferred substrate for the Bloom’s syndrome helicase. Nucleic Acids Res.,  2006, 34(8), 2269-2279.
[http://dx.doi.org/10.1093/nar/gkl258] [PMID:  16670433] 
[42] 
Karow, J.K.; Chakraverty, R.K.; Hickson, I.D. The Bloom’s syndrome gene product is a 3′-5′ DNA helicase. J. Biol. Chem.,  1997, 272(49), 30611-30614.
[http://dx.doi.org/10.1074/jbc.272.49.30611] [PMID:  9388193] 
[43] 
Mohaghegh, P.; Karow, J.K.; Brosh, R.M., Jr; Bohr, V.A.; Hickson, I.D. The Bloom’s and Werner’s syndrome proteins are DNA structure-specific helicases. Nucleic Acids Res.,  2001, 29(13), 2843-2849.
[http://dx.doi.org/10.1093/nar/29.13.2843] [PMID:  11433031] 
[44] 
Wu, L.; Davies, S.L.; North, P.S.; Goulaouic, H.; Riou, J.F.; Turley, H.; Gatter, K.C.; Hickson, I.D. The Bloom’s syndrome gene product interacts with topoisomerase III. J. Biol. Chem.,  2000, 275(13), 9636-9644.
[http://dx.doi.org/10.1074/jbc.275.13.9636] [PMID:  10734115] 
[45] 
Wu, L.; Bachrati, C.Z.; Ou, J.; Xu, C.; Yin, J.; Chang, M.; Wang, W.; Li, L.; Brown, G.W.; Hickson, I.D. BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates. Proc. Natl. Acad. Sci. USA,  2006, 103(11), 4068-4073.
[http://dx.doi.org/10.1073/pnas.0508295103] [PMID:  16537486] 
[46] 
Singh, T.R.; Ali, A.M.; Busygina, V.; Raynard, S.; Fan, Q.; Du, C.H.; Andreassen, P.R.; Sung, P.; Meetei, A.R. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome. Genes Dev.,  2008, 22(20), 2856-2868.
[http://dx.doi.org/10.1101/gad.1725108] [PMID:  18923083] 
[47] 
Karow, J.K.; Constantinou, A.; Li, J.L.; West, S.C.; Hickson, I.D. The Bloom’s syndrome gene product promotes branch migration of holliday junctions. Proc. Natl. Acad. Sci. USA,  2000, 97(12), 6504-6508.
[http://dx.doi.org/10.1073/pnas.100448097] [PMID:  10823897] 
[48] 
Bizard, A.H.; Hickson, I.D. The dissolution of double Holliday junctions. Cold Spring Harb. Perspect. Biol.,  2014, 6(7) a016477
[http://dx.doi.org/10.1101/cshperspect.a016477] [PMID:  24984776] 
[49] 
Kitao, S.; Ohsugi, I.; Ichikawa, K.; Goto, M.; Furuichi, Y.; Shimamoto, A. Cloning of two new human helicase genes of the RecQ family: Biological significance of multiple species in higher eukaryotes. Genomics,  1998, 54(3), 443-452.
[http://dx.doi.org/10.1006/geno.1998.5595] [PMID:  9878247] 
[50] 
Bischof, O.; Kim, S.H.; Irving, J.; Beresten, S.; Ellis, N.A.; Campisi, J. Regulation and localization of the Bloom syndrome protein in response to DNA damage. J. Cell Biol.,  2001, 153(2), 367-380.
[http://dx.doi.org/10.1083/jcb.153.2.367] [PMID:  11309417] 
[51] 
Barefield, C.; Karlseder, J. The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures. Nucleic Acids Res.,  2012, 40(15), 7358-7367.
[http://dx.doi.org/10.1093/nar/gks407] [PMID:  22576367] 
[52] 
Eladad, S.; Ye, T.Z.; Hu, P.; Leversha, M.; Beresten, S.; Matunis, M.J.; Ellis, N.A. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Hum. Mol. Genet.,  2005, 14(10), 1351-1365.
[http://dx.doi.org/10.1093/hmg/ddi145] [PMID:  15829507] 
[53] 
Goss, K.H.; Risinger, M.A.; Kordich, J.J.; Sanz, M.M.; Straughen, J.E.; Slovek, L.E.; Capobianco, A.J.; German, J.; Boivin, G.P.; Groden, J. Enhanced tumor formation in mice heterozygous for BLM mutation. Science,  2002, 297(5589), 2051-2053.
[http://dx.doi.org/10.1126/science.1074340] [PMID:  12242442] 
[54] 
McDaniel, L.D.; Chester, N.; Watson, M.; Borowsky, A.D.; Leder, P.; Schultz, R.A. Chromosome instability and tumor predisposition inversely correlate with BLM protein levels. DNA Repair (Amst.),  2003, 2(12), 1387-1404.
[http://dx.doi.org/10.1016/j.dnarep.2003.08.006] [PMID:  14642567] 
[55] 
Lauper, J.M.; Krause, A.; Vaughan, T.L.; Monnat, R.J., Jr Spectrum and risk of neoplasia in Werner syndrome: A systematic review. PLoS One,  2013, 8(4) e59709
[http://dx.doi.org/10.1371/journal.pone.0059709] [PMID:  23573208] 
[56] 
Epstein, C.J.; Martin, G.M.; Schultz, A.L.; Motulsky, A.G. Werner’s syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore),  1966, 45(3), 177-221.
[http://dx.doi.org/10.1097/00005792-196605000-00001] [PMID:  5327241] 
[57] 
Oshima, J.; Sidorova, J.M.; Monnat, R.J., Jr Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res. Rev.,  2017, 33, 105-114.
[PMID: 26993153] 
[58] 
Lebel, M.; Leder, P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl. Acad. Sci. USA,  1998, 95(22), 13097-13102.
[http://dx.doi.org/10.1073/pnas.95.22.13097] [PMID:  9789047] 
[59] 
Lombard, D.B.; Beard, C.; Johnson, B.; Marciniak, R.A.; Dausman, J.; Bronson, R.; Buhlmann, J.E.; Lipman, R.; Curry, R.; Sharpe, A.; Jaenisch, R.; Guarente, L. Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Mol. Cell. Biol.,  2000, 20(9), 3286-3291.
[http://dx.doi.org/10.1128/MCB.20.9.3286-3291.2000] [PMID:  10757812] 
[60] 
Futami, K.; Furuichi, Y. RECQL1 and WRN DNA repair helicases: Potential therapeutic targets and proliferative markers against cancers. Front. Genet.,  2015, 5, 441.
[http://dx.doi.org/10.3389/fgene.2014.00441] [PMID:  25620975] 
[61] 
Huang, S.; Li, B.; Gray, M.D.; Oshima, J.; Mian, I.S.; Campisi, J. The premature ageing syndrome protein, WRN, is a 3′-->5′ exonuclease. Nat. Genet.,  1998, 20(2), 114-116.
[http://dx.doi.org/10.1038/2410] [PMID:  9771700] 
[62] 
Ozgenc, A.; Loeb, L.A. Current advances in unraveling the function of the Werner syndrome protein. Mutat. Res.,  2005, 577(1-2), 237-251.
[http://dx.doi.org/10.1016/j.mrfmmm.2005.03.020] [PMID:  15946710] 
[63] 
Shen, J.C.; Loeb, L.A. Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA. Nucleic Acids Res.,  2000, 28(17), 3260-3268.
[http://dx.doi.org/10.1093/nar/28.17.3260] [PMID:  10954593] 
[64] 
Huang, S.; Beresten, S.; Li, B.; Oshima, J.; Ellis, N.A.; Campisi, J. Characterization of the human and mouse WRN 3′-->5′ exonuclease. Nucleic Acids Res.,  2000, 28(12), 2396-2405.
[http://dx.doi.org/10.1093/nar/28.12.2396] [PMID:  10871373] 
[65] 
Thangavel, S.; Berti, M.; Levikova, M.; Pinto, C.; Gomathinayagam, S.; Vujanovic, M.; Zellweger, R.; Moore, H.; Lee, E.H.; Hendrickson, E.A.; Cejka, P.; Stewart, S.; Lopes, M.; Vindigni, A. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol.,  2015, 208(5), 545-562.
[http://dx.doi.org/10.1083/jcb.201406100] [PMID:  25733713] 
[66] 
Chan, E.M.; Shibue, T.; McFarland, J.M.; Gaeta, B.; Ghandi, M.; Dumont, N.; Gonzalez, A.; McPartlan, J.S.; Li, T.; Zhang, Y.; Bin, Liu. J.; Lazaro, J.B.; Gu, P.; Piett, C.G.; Apffel, A.; Ali, S.O.; Deasy, R.; Keskula, P.; Ng, R.W.S.; Roberts, E.A.; Reznichenko, E.; Leung, L.; Alimova, M.; Schenone, M.; Islam, M.; Maruvka, Y.E.; Liu, Y.; Roper, J.; Raghavan, S.; Giannakis, M.; Tseng, Y.Y.; Nagel, Z.D.; D’Andrea, A.; Root, D.E.; Boehm, J.S.; Getz, G.; Chang, S.; Golub, T.R.; Tsherniak, A.; Vazquez, F.; Bass, A.J.. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature,  2019, 568(7753), 551-556.
[http://dx.doi.org/10.1038/s41586-019-1102-x] [PMID:  30971823] 
[67] 
Lu, L.; Jin, W.; Wang, L.L. Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders. Ageing Res. Rev.,  2017, 33, 30-35.
[PMID: 27287744] 
[68] 
Croteau, D.L.; Singh, D.K.; Hoh Ferrarelli, L.; Lu, H.; Bohr, V.A. RECQL4 in genomic instability and aging. Trends Genet.,  2012, 28(12), 624-631.
[http://dx.doi.org/10.1016/j.tig.2012.08.003] [PMID:  22940096] 
[69] 
Croteau, D.L.; Rossi, M.L.; Canugovi, C.; Tian, J.; Sykora, P.; Ramamoorthy, M.; Wang, Z.M.; Singh, D.K.; Akbari, M.; Kasiviswanathan, R.; Copeland, W.C.; Bohr, V.A. RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity. Aging Cell,  2012, 11(3), 456-466.
[http://dx.doi.org/10.1111/j.1474-9726.2012.00803.x] [PMID:  22296597] 
[70] 
Sangrithi, M.N.; Bernal, J.A.; Madine, M.; Philpott, A.; Lee, J.; Dunphy, W.G.; Venkitaraman, A.R. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Cell,  2005, 121(6), 887-898.
[http://dx.doi.org/10.1016/j.cell.2005.05.015] [PMID:  15960976] 
[71] 
Ichikawa, K.; Noda, T.; Furuichi, Y. Preparation of the gene targeted knockout mice for human premature aging diseases, Werner syndrome, and Rothmund-Thomson syndrome caused by the mutation of DNA helicases. Nippon Yakurigaku Zasshi,  2002, 119(4), 219-226.
[http://dx.doi.org/10.1254/fpj.119.219] [PMID:  11979727] 
[72] 
Ghosh, A.K.; Rossi, M.L.; Singh, D.K.; Dunn, C.; Ramamoorthy, M.; Croteau, D.L.; Liu, Y.; Bohr, V.A. RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J. Biol. Chem.,  2012, 287(1), 196-209.
[http://dx.doi.org/10.1074/jbc.M111.295063] [PMID:  22039056] 
[73] 
Singh, D.K.; Popuri, V.; Kulikowicz, T.; Shevelev, I.; Ghosh, A.K.; Ramamoorthy, M.; Rossi, M.L.; Janscak, P.; Croteau, D.L.; Bohr, V.A. The human RecQ helicases BLM and RecQL4 cooperate to preserve genome stability. Nucleic Acids Res.,  2012, 40(14), 6632-6648.
[http://dx.doi.org/10.1093/nar/gks349] [PMID:  22544709] 
[74] 
Popuri, V.; Tadokoro, T.; Croteau, D.L.; Bohr, V.A. Human RecQL5: Guarding the crossroads of DNA replication and transcription and providing backup capability. Crit. Rev. Biochem. Mol. Biol.,  2013, 48(3), 289-299.
[http://dx.doi.org/10.3109/10409238.2013.792770] [PMID:  23627586] 
[75] 
Ren, H.; Dou, S.X.; Zhang, X.D.; Wang, P.Y.; Kanagaraj, R.; Liu, J.L.; Janscak, P.; Hu, J.S.; Xi, X.G. The zinc-binding motif of human RecQ5beta suppresses the intrinsic strand-annealing activity of its DExH helicase domain and is essential for the helicase activity of the enzyme. Biochem. J.,  2008, 412(3), 425-433.
[http://dx.doi.org/10.1042/BJ20071150] [PMID:  18290761] 
[76] 
Garcia, P.L.; Liu, Y.; Jiricny, J.; West, S.C.; Janscak, P. Human RECQ5beta, a protein with DNA helicase and strand-annealing activities in a single polypeptide. EMBO J.,  2004, 23(14), 2882-2891.
[http://dx.doi.org/10.1038/sj.emboj.7600301] [PMID:  15241474] 
[77] 
Khadka, P.; Croteau, D.L.; Bohr, V.A. RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins. DNA Repair (Amst.),  2016, 37, 53-66.
[http://dx.doi.org/10.1016/j.dnarep.2015.11.005] [PMID:  26717024] 
[78] 
He, Y.J.; Qiao, Z.Y.; Gao, B.; Zhang, X.H.; Wen, Y.Y. Association between RecQL5 genetic polymorphisms and susceptibility to breast cancer. Tumour Biol.,  2014, 35(12), 12201-12204.
[http://dx.doi.org/10.1007/s13277-014-2528-2] [PMID:  25394896] 
[79] 
Tadokoro, T.; Ramamoorthy, M.; Popuri, V.; May, A.; Tian, J.; Sykora, P.; Rybanska, I.; Wilson, D.M., III; Croteau, D.L.; Bohr, V.A. Human RECQL5 participates in the removal of endogenous DNA damage. Mol. Biol. Cell,  2012, 23(21), 4273-4285.
[http://dx.doi.org/10.1091/mbc.e12-02-0110] [PMID:  22973052] 
[80] 
Popuri, V.; Ramamoorthy, M.; Tadokoro, T.; Singh, D.K.; Karmakar, P.; Croteau, D.L.; Bohr, V.A. Recruitment and retention dynamics of RecQL5 at DNA double strand break sites. DNA Repair (Amst.),  2012, 11(7), 624-635.
[http://dx.doi.org/10.1016/j.dnarep.2012.05.001] [PMID:  22633600] 
[81] 
Popuri, V.; Huang, J.; Ramamoorthy, M.; Tadokoro, T.; Croteau, D.L.; Bohr, V.A. RecQL5 plays co-operative and complementary roles with WRN syndrome helicase. Nucleic Acids Res.,  2013, 41(2), 881-899.
[http://dx.doi.org/10.1093/nar/gks1134] [PMID:  23180761] 
[82] 
Schwendener, S.; Raynard, S.; Paliwal, S.; Cheng, A.; Kanagaraj, R.; Shevelev, I.; Stark, J.M.; Sung, P.; Janscak, P. Physical interaction of RecQ5 helicase with RAD51 facilitates its anti-recombinase activity. J. Biol. Chem.,  2010, 285(21), 15739-15745.
[http://dx.doi.org/10.1074/jbc.M110.110478] [PMID:  20348101] 
[83] 
Rodríguez-López, A.M.; Jackson, D.A.; Iborra, F.; Cox, L.S. Asymmetry of DNA replication fork progression in Werner’s syndrome. Aging Cell,  2002, 1(1), 30-39.
[http://dx.doi.org/10.1046/j.1474-9728.2002.00002.x] [PMID:  12882351] 
[84] 
Machwe, A.; Karale, R.; Xu, X.; Liu, Y.; Orren, D.K. The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks. Biochemistry,  2011, 50(32), 6774-6788.
[http://dx.doi.org/10.1021/bi2001054] [PMID:  21736299] 
[85] 
Nimonkar, A.V.; Genschel, J.; Kinoshita, E.; Polaczek, P.; Campbell, J.L.; Wyman, C.; Modrich, P.; Kowalczykowski, S.C. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev.,  2011, 25(4), 350-362.
[http://dx.doi.org/10.1101/gad.2003811] [PMID:  21325134] 
[86] 
Sturzenegger, A.; Burdova, K.; Kanagaraj, R.; Levikova, M.; Pinto, C.; Cejka, P.; Janscak, P. DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J. Biol. Chem.,  2014, 289(39), 27314-27326.
[http://dx.doi.org/10.1074/jbc.M114.578823] [PMID:  25122754] 
[87] 
Ammazzalorso, F.; Pirzio, L.M.; Bignami, M.; Franchitto, A.; Pichierri, P. ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J.,  2010, 29(18), 3156-3169.
[http://dx.doi.org/10.1038/emboj.2010.205] [PMID:  20802463] 
[88] 
Davies, S.L.; North, P.S.; Dart, A.; Lakin, N.D.; Hickson, I.D. Phosphorylation of the Bloom’s syndrome helicase and its role in recovery from S-phase arrest. Mol. Cell. Biol.,  2004, 24(3), 1279-1291.
[http://dx.doi.org/10.1128/MCB.24.3.1279-1291.2004] [PMID:  14729972] 
[89] 
Shin, S.; Lee, J.; Yoo, S.; Kulikowicz, T.; Bohr, V.A.; Ahn, B.; Hohng, S. Active control of repetitive structural transitions between replication forks and holliday junctions by Werner Syndrome Helicase. Structure,  2016, 24(8), 1292-1300.
[http://dx.doi.org/10.1016/j.str.2016.06.004] [PMID:  27427477] 
[90] 
Ralf, C.; Hickson, I.D.; Wu, L. The Bloom’s syndrome helicase can promote the regression of a model replication fork. J. Biol. Chem.,  2006, 281(32), 22839-22846.
[http://dx.doi.org/10.1074/jbc.M604268200] [PMID:  16766518] 
[91] 
Davies, S.L.; North, P.S.; Hickson, I.D. Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat. Struct. Mol. Biol.,  2007, 14(7), 677-679.
[http://dx.doi.org/10.1038/nsmb1267] [PMID:  17603497] 
[92] 
Kanagaraj, R.; Saydam, N.; Garcia, P.L.; Zheng, L.; Janscak, P. Human RecQ5beta helicase promotes strand exchange on synthetic DNA structures resembling a stalled replication fork. Nucleic Acids Res.,  2006, 34(18), 5217-5231.
[http://dx.doi.org/10.1093/nar/gkl677] [PMID:  17003056] 
[93] 
Ying, S.; Chen, Z.; Medhurst, A.L.; Neal, J.A.; Bao, Z.; Mortusewicz, O.; McGouran, J.; Song, X.; Shen, H.; Hamdy, F.C.; Kessler, B.M.; Meek, K.; Helleday, T. DNA-PKcs and PARP1 bind to unresected stalled DNA replication forks where they recruit XRCC1 to mediate repair. Cancer Res.,  2016, 76(5), 1078-1088.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0608] [PMID:  26603896] 
[94] 
De Lorenzo, S.B.; Patel, A.G.; Hurley, R.M.; Kaufmann, S.H. The Elephant and the blind men: Making sense of PARP inhibitors in homologous recombination deficient tumor cells. Front. Oncol.,  2013, 3, 228.
[http://dx.doi.org/10.3389/fonc.2013.00228] [PMID:  24062981] 
[95] 
Zhao, L.; So, C.W. PARP-inhibitor-induced synthetic lethality for acute myeloid leukemia treatment. Exp. Hematol.,  2016, 44(10), 902-907.
[http://dx.doi.org/10.1016/j.exphem.2016.07.007] [PMID:  27473567] 
[96] 
Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature,  2005, 434(7035), 913-917.
[http://dx.doi.org/10.1038/nature03443] [PMID:  15829966] 
[97] 
Rouleau, M.; Patel, A.; Hendzel, M.J.; Kaufmann, S.H.; Poirier, G.G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer,  2010, 10(4), 293-301.
[http://dx.doi.org/10.1038/nrc2812] [PMID:  20200537] 
[98] 
Lord, C.J.; Ashworth, A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med.,  2013, 19(11), 1381-1388.
[http://dx.doi.org/10.1038/nm.3369] [PMID:  24202391] 
[99] 
Chastain, M.; Zhou, Q.; Shiva, O.; Fadri-Moskwik, M.; Whitmore, L.; Jia, P.; Dai, X.; Huang, C.; Ye, P.; Chai, W. Human CST facilitates genome-wide RAD51 recruitment to GC-rich repetitive sequences in response to replication stress. Cell Rep.,  2016, 16(7), 2048.
[http://dx.doi.org/10.1016/j.celrep.2016.08.008] [PMID:  27533181] 
[100] 
Somyajit, K.; Saxena, S.; Babu, S.; Mishra, A.; Nagaraju, G. Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart. Nucleic Acids Res.,  2015, 43(20), 9835-9855.
[http://dx.doi.org/10.1093/nar/gkv880] [PMID:  26354865] 
[101] 
Bansbach, C.E.; Bétous, R.; Lovejoy, C.A.; Glick, G.G.; Cortez, D. The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev.,  2009, 23(20), 2405-2414.
[http://dx.doi.org/10.1101/gad.1839909] [PMID:  19793861] 
[102] 
Poole, L.A.; Zhao, R.; Glick, G.G.; Lovejoy, C.A.; Eischen, C.M.; Cortez, D. SMARCAL1 maintains telomere integrity during DNA replication. Proc. Natl. Acad. Sci. USA,  2015, 112(48), 14864-14869.
[http://dx.doi.org/10.1073/pnas.1510750112] [PMID:  26578802] 
[103] 
Bétous, R.; Couch, F.B.; Mason, A.C.; Eichman, B.F.; Manosas, M.; Cortez, D. Substrate-selective repair and restart of replication forks by DNA translocases. Cell Rep.,  2013, 3(6), 1958-1969.
[http://dx.doi.org/10.1016/j.celrep.2013.05.002] [PMID:  23746452] 
[104] 
Ciccia, A.; Bredemeyer, A.L.; Sowa, M.E.; Terret, M.E.; Jallepalli, P.V.; Harper, J.W.; Elledge, S.J. The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart. Genes Dev.,  2009, 23(20), 2415-2425.
[http://dx.doi.org/10.1101/gad.1832309] [PMID:  19793862] 
[105] 
Bétous, R.; Mason, A.C.; Rambo, R.P.; Bansbach, C.E.; Badu-Nkansah, A.; Sirbu, B.M.; Eichman, B.F.; Cortez, D. SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev.,  2012, 26(2), 151-162.
[http://dx.doi.org/10.1101/gad.178459.111] [PMID:  22279047] 
[106] 
Bhat, K.P.; Bétous, R.; Cortez, D. High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1-dependent replication fork remodeling. J. Biol. Chem.,  2015, 290(7), 4110-4117.
[http://dx.doi.org/10.1074/jbc.M114.627083] [PMID:  25552480] 
[107] 
Petermann, E.; Helleday, T. Pathways of mammalian replication fork restart. Nat. Rev. Mol. Cell Biol.,  2010, 11(10), 683-687.
[http://dx.doi.org/10.1038/nrm2974] [PMID:  20842177] 
[108] 
Couch, F.B.; Bansbach, C.E.; Driscoll, R.; Luzwick, J.W.; Glick, G.G.; Bétous, R.; Carroll, C.M.; Jung, S.Y.; Qin, J.; Cimprich, K.A.; Cortez, D. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev.,  2013, 27(14), 1610-1623.
[http://dx.doi.org/10.1101/gad.214080.113] [PMID:  23873943] 
[109] 
Carroll, C.; Bansbach, C.E.; Zhao, R.; Jung, S.Y.; Qin, J.; Cortez, D. Phosphorylation of a C-terminal auto-inhibitory domain increases SMARCAL1 activity. Nucleic Acids Res.,  2014, 42(2), 918-925.
[http://dx.doi.org/10.1093/nar/gkt929] [PMID:  24150942] 
[110] 
Boerkoel, C.F.; Takashima, H.; John, J.; Yan, J.; Stankiewicz, P.; Rosenbarker, L.; André, J.L.; Bogdanovic, R.; Burguet, A.; Cockfield, S.; Cordeiro, I.; Fründ, S.; Illies, F.; Joseph, M.; Kaitila, I.; Lama, G.; Loirat, C.; McLeod, D.R.; Milford, D.V.; Petty, E.M.; Rodrigo, F.; Saraiva, J.M.; Schmidt, B.; Smith, G.C.; Spranger, J.; Stein, A.; Thiele, H.; Tizard, J.; Weksberg, R.; Lupski, J.R.; Stockton, D.W. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet.,  2002, 30(2), 215-220.
[http://dx.doi.org/10.1038/ng821] [PMID:  11799392] 
[111] 
Ciccia, A.; Nimonkar, A.V.; Hu, Y.; Hajdu, I.; Achar, Y.J.; Izhar, L.; Petit, S.A.; Adamson, B.; Yoon, J.C.; Kowalczykowski, S.C.; Livingston, D.M.; Haracska, L.; Elledge, S.J. Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol. Cell,  2012, 47(3), 396-409.
[http://dx.doi.org/10.1016/j.molcel.2012.05.024] [PMID:  22704558] 
[112] 
Yuan, J.; Ghosal, G.; Chen, J. The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Mol. Cell,  2012, 47(3), 410-421.
[http://dx.doi.org/10.1016/j.molcel.2012.05.025] [PMID:  22705370] 
[113] 
Weston, R.; Peeters, H.; Ahel, D. ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. Genes Dev.,  2012, 26(14), 1558-1572.
[http://dx.doi.org/10.1101/gad.193516.112] [PMID:  22759634] 
[114] 
Bugreev, D.V.; Rossi, M.J.; Mazin, A.V. Cooperation of RAD51 and RAD54 in regression of a model replication fork. Nucleic Acids Res.,  2011, 39(6), 2153-2164.
[http://dx.doi.org/10.1093/nar/gkq1139] [PMID:  21097884] 
[115] 
Bugreev, D.V.; Mazina, O.M.; Mazin, A.V. Rad54 protein promotes branch migration of Holliday junctions. Nature,  2006, 442(7102), 590-593.
[http://dx.doi.org/10.1038/nature04889] [PMID:  16862129] 
[116] 
Achar, Y.J.; Balogh, D.; Neculai, D.; Juhasz, S.; Morocz, M.; Gali, H.; Dhe-Paganon, S.; Venclovas, Č.; Haracska, L. Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling. Nucleic Acids Res.,  2015, 43(21), 10277-10291.
[http://dx.doi.org/10.1093/nar/gkv896] [PMID:  26350214] 
[117] 
Kile, A.C.; Chavez, D.A.; Bacal, J.; Eldirany, S.; Korzhnev, D.M.; Bezsonova, I.; Eichman, B.F.; Cimprich, K.A. HLTF’s ancient HIRAN domain binds 3′ DNA ends to drive replication fork reversal. Mol. Cell,  2015, 58(6), 1090-1100.
[http://dx.doi.org/10.1016/j.molcel.2015.05.013] [PMID:  26051180] 
[118] 
Whitby, M.C. The FANCM family of DNA helicases/translocases. DNA Repair (Amst.),  2010, 9(3), 224-236.
[http://dx.doi.org/10.1016/j.dnarep.2009.12.012] [PMID:  20117061] 
[119] 
Gari, K.; Décaillet, C.; Stasiak, A.Z.; Stasiak, A.; Constantinou, A. The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. Mol. Cell,  2008, 29(1), 141-148.
[http://dx.doi.org/10.1016/j.molcel.2007.11.032] [PMID:  18206976] 
[120] 
Gari, K.; Décaillet, C.; Delannoy, M.; Wu, L.; Constantinou, A. Remodeling of DNA replication structures by the branch point translocase FANCM. Proc. Natl. Acad. Sci. USA,  2008, 105(42), 16107-16112.
[http://dx.doi.org/10.1073/pnas.0804777105] [PMID:  18843105] 
[121] 
Hampp, S.; Kiessling, T.; Buechle, K.; Mansilla, S.F.; Thomale, J.; Rall, M.; Ahn, J.; Pospiech, H.; Gottifredi, V.; Wiesmüller, L. DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression. Proc. Natl. Acad. Sci. USA,  2016, 113(30), E4311-E4319.
[http://dx.doi.org/10.1073/pnas.1605828113] [PMID:  27407148] 
[122] 
Rosenthal, A.S.; Dexheimer, T.S.; Gileadi, O.; Nguyen, G.H.; Chu, W.K.; Hickson, I.D.; Jadhav, A.; Simeonov, A.; Maloney, D.J. Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase. Bioorg. Med. Chem. Lett.,  2013, 23(20), 5660-5666.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.025] [PMID:  24012121] 
[123] 
Sommers, J.A.; Kulikowicz, T.; Croteau, D.L.; Dexheimer, T.; Dorjsuren, D.; Jadhav, A.; Maloney, D.J.; Simeonov, A.; Bohr, V.A.; Brosh, R.M., Jr A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS One,  2019, 14(1) e0210525
[http://dx.doi.org/10.1371/journal.pone.0210525] [PMID:  30625228] 
[124] 
Nguyen, G.H.; Dexheimer, T.S.; Rosenthal, A.S.; Chu, W.K.; Singh, D.K.; Mosedale, G.; Bachrati, C.Z.; Schultz, L.; Sakurai, M.; Savitsky, P.; Abu, M.; McHugh, P.J.; Bohr, V.A.; Harris, C.C.; Jadhav, A.; Gileadi, O.; Maloney, D.J.; Simeonov, A.; Hickson, I.D. A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells. Chem. Biol.,  2013, 20(1), 55-62.
[http://dx.doi.org/10.1016/j.chembiol.2012.10.016] [PMID:  23352139] 
[125] 
Aggarwal, M.; Sommers, J.A.; Shoemaker, R.H.; Brosh, R.M., Jr Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress. Proc. Natl. Acad. Sci. USA,  2011, 108(4), 1525-1530.
[http://dx.doi.org/10.1073/pnas.1006423108] [PMID:  21220316] 
[126] 
Banerjee, T.; Aggarwal, M.; Brosh, R.M., Jr A new development in DNA repair modulation: discovery of a BLM helicase inhibitor. Cell Cycle,  2013, 12(5), 713-714.
[http://dx.doi.org/10.4161/cc.23953] [PMID:  23422862] 
[127] 
Aggarwal, M.; Banerjee, T.; Sommers, J.A.; Iannascoli, C.; Pichierri, P.; Shoemaker, R.H.; Brosh, R.M., Jr Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional fanconi anemia pathway. Cancer Res.,  2013, 73(17), 5497-5507.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2975] [PMID:  23867477] 
[128] 
Moles, R.; Bai, X.T.; Chaib-Mezrag, H.; Nicot, C. WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells. J. Hematol. Oncol.,  2016, 9(1), 121.
[http://dx.doi.org/10.1186/s13045-016-0352-4] [PMID:  27829440] 
[129] 
Aggarwal, M.; Banerjee, T.; Sommers, J.A.; Brosh, R.M., Jr Targeting an Achilles’ heel of cancer with a WRN helicase inhibitor. Cell Cycle,  2013, 12(20), 3329-3335.
[http://dx.doi.org/10.4161/cc.26320] [PMID:  24036544] 
[130] 
Brosh, R.M., Jr; Karow, J.K.; White, E.J.; Shaw, N.D.; Hickson, I.D.; Bohr, V.A. Potent inhibition of Werner and Bloom helicases by DNA minor groove binding drugs. Nucleic Acids Res.,  2000, 28(12), 2420-2430.
[http://dx.doi.org/10.1093/nar/28.12.2420] [PMID:  10871376] 
[131] 
Li, J.L.; Harrison, R.J.; Reszka, A.P.; Brosh, R.M., Jr; Bohr, V.A.; Neidle, S.; Hickson, I.D. Inhibition of the Bloom’s and Werner’s syndrome helicases by G-quadruplex interacting ligands. Biochemistry,  2001, 40(50), 15194-15202.
[http://dx.doi.org/10.1021/bi011067h] [PMID:  11735402] 
[132] 
Karow, J.K.; Wu, L.; Hickson, I.D. RecQ family helicases: Roles in cancer and aging. Curr. Opin. Genet. Dev.,  2000, 10(1), 32-38.
[http://dx.doi.org/10.1016/S0959-437X(99)00039-8] [PMID:  10679384] 
[133] 
Yin, Q.K.; Wang, C.X.; Wang, Y.Q.; Guo, Q.L.; Zhang, Z.L.; Ou, T.M.; Huang, S.L.; Li, D.; Wang, H.G.; Tan, J.H.; Chen, S.B.; Huang, Z.S. Discovery of isaindigotone derivatives as novel Bloom’s Syndrome Protein (BLM) helicase inhibitors that disrupt the BLM/DNA Interactions and regulate the homologous recombination repair. J. Med. Chem.,  2019, 62(6), 3147-3162.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00083] [PMID:  30827110] 
[134] 
Liu, W.; Zhou, M.; Li, Z.; Li, H.; Polaczek, P.; Dai, H.; Wu, Q.; Liu, C.; Karanja, K.K.; Popuri, V.; Shan, S.O.; Schlacher, K.; Zheng, L.; Campbell, J.L.; Shen, B. A selective small molecule DNA2 inhibitor for sensitization of human cancer cells to chemotherapy. EBioMedicine,  2016, 6, 73-86.
[http://dx.doi.org/10.1016/j.ebiom.2016.02.043] [PMID:  27211550] 
[135] 
Kumar, S.; Peng, X.; Daley, J.; Yang, L.; Shen, J.; Nguyen, N.; Bae, G.; Niu, H.; Peng, Y.; Hsieh, H.J.; Wang, L.; Rao, C.; Stephan, C.C.; Sung, P.; Ira, G.; Peng, G. Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells. Oncogenesis,  2017, 6(4) e319
[http://dx.doi.org/10.1038/oncsis.2017.15] [PMID:  28414320] 
[136] 
Sharma, S.; Brosh, R.M., Jr Human RecQ1 is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS One,  2007, 2(12) e1297
[http://dx.doi.org/10.1371/journal.pone.0001297] [PMID:  18074021] 
[137] 
Futami, K.; Kumagai, E.; Makino, H.; Sato, A.; Takagi, M.; Shimamoto, A.; Furuichi, Y. Anticancer activity of RecQL1 helicase siRNA in mouse xenograft models. Cancer Sci.,  2008, 99(6), 1227-1236.
[http://dx.doi.org/10.1111/j.1349-7006.2008.00794.x] [PMID:  18422747] 
[138] 
Futami, K.; Kumagai, E.; Makino, H.; Goto, H.; Takagi, M.; Shimamoto, A.; Furuichi, Y. Induction of mitotic cell death in cancer cells by small interference RNA suppressing the expression of RecQL1 helicase. Cancer Sci.,  2008, 99(1), 71-80.
[PMID: 17953710] 
[139] 
Futami, K.; Ogasawara, S.; Goto, H.; Yano, H.; Furuichi, Y. RecQL1 DNA repair helicase: A potential tumor marker and therapeutic target against hepatocellular carcinoma. Int. J. Mol. Med.,  2010, 25(4), 537-545.
[PMID: 20198302] 
[140] 
Arai, A.; Chano, T.; Futami, K.; Furuichi, Y.; Ikebuchi, K.; Inui, T.; Tameno, H.; Ochi, Y.; Shimada, T.; Hisa, Y.; Okabe, H. RECQL1 and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma. Cancer Res.,  2011, 71(13), 4598-4607.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-0320] [PMID:  21571861] 
[141] 
Mendoza-Maldonado, R.; Faoro, V.; Bajpai, S.; Berti, M.; Odreman, F.; Vindigni, M.; Ius, T.; Ghasemian, A.; Bonin, S.; Skrap, M.; Stanta, G.; Vindigni, A. The human RecQ1 helicase is highly expressed in glioblastoma and plays an important role in tumor cell proliferation. Mol. Cancer,  2011, 10, 83.
[http://dx.doi.org/10.1186/1476-4598-10-83] [PMID:  21752281] 
[142] 
Popuri, V.; Croteau, D.L.; Brosh, R.M., Jr; Bohr, V.A. RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. Cell Cycle,  2012, 11(22), 4252-4265.
[http://dx.doi.org/10.4161/cc.22581] [PMID:  23095637] 
[143] 
Li, D.; Frazier, M.; Evans, D.B.; Hess, K.R.; Crane, C.H.; Jiao, L.; Abbruzzese, J.L. Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer. J. Clin. Oncol.,  2006, 24(11), 1720-1728.
[http://dx.doi.org/10.1200/JCO.2005.04.4206] [PMID:  16520463] 
[144] 
Li, D.; Liu, H.; Jiao, L.; Chang, D.Z.; Beinart, G.; Wolff, R.A.; Evans, D.B.; Hassan, M.M.; Abbruzzese, J.L. Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival. Cancer Res.,  2006, 66(6), 3323-3330.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3032] [PMID:  16540687] 
[145] 
Cybulski, C.; Carrot-Zhang, J.; Kluźniak, W.; Rivera, B.; Kashyap, A.; Wokołorczyk, D.; Giroux, S.; Nadaf, J.; Hamel, N.; Zhang, S.; Huzarski, T.; Gronwald, J.; Byrski, T.; Szwiec, M.; Jakubowska, A.; Rudnicka, H.; Lener, M.; Masojć, B.; Tonin, P.N.; Rousseau, F.; Górski, B.; Dębniak, T.; Majewski, J.; Lubiński, J.; Foulkes, W.D.; Narod, S.A.; Akbari, M.R. Germline RecQL mutations are associated with breast cancer susceptibility. Nat. Genet.,  2015, 47(6), 643-646.
[http://dx.doi.org/10.1038/ng.3284] [PMID:  25915596] 
[146] 
Sun, J.; Wang, Y.; Xia, Y.; Xu, Y.; Ouyang, T.; Li, J.; Wang, T.; Fan, Z.; Fan, T.; Lin, B.; Lou, H.; Xie, Y. Mutations in RecQL gene are associated with predisposition to breast cancer. PLoS Genet.,  2015, 11(5) e1005228
[http://dx.doi.org/10.1371/journal.pgen.1005228] [PMID:  25945795] 
[147] 
Kwong, A.; Shin, V.Y.; Cheuk, I.W.Y.; Chen, J.; Au, C.H.; Ho, D.N.; Chan, T.L.; Ma, E.S.K.; Akbari, M.R.; Narod, S.A. Germline RECQL mutations in high risk Chinese breast cancer patients. Breast Cancer Res. Treat.,  2016, 157(2), 211-215.
[http://dx.doi.org/10.1007/s10549-016-3784-1] [PMID:  27125668] 
[148] 
Futami, K.; Takagi, M.; Shimamoto, A.; Sugimoto, M.; Furuichi, Y. Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase. Biol. Pharm. Bull.,  2007, 30(10), 1958-1961.
[http://dx.doi.org/10.1248/bpb.30.1958] [PMID:  17917271] 
[149] 
Cheng, W.H.; Wu, R.T.; Wu, M.; Rocourt, C.R.; Carrillo, J.A.; Song, J.; Bohr, C.T.; Tzeng, T.J. Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death. Biochem. Biophys. Res. Commun.,  2012, 420(1), 24-28.
[http://dx.doi.org/10.1016/j.bbrc.2012.02.104] [PMID:  22390926] 
[150] 
Lee, S.Y.; Lee, H.; Kim, E.S.; Park, S.; Lee, J.; Ahn, B. WRN translocation from nucleolus to nucleoplasm is regulated by SIRT1 and required for DNA repair and the development of chemoresistance. Mutat. Res.,  2015, 774, 40-48.
[http://dx.doi.org/10.1016/j.mrfmmm.2015.03.001] [PMID:  25801465] 
[151] 
Mao, F.J.; Sidorova, J.M.; Lauper, J.M.; Emond, M.J.; Monnat, R.J. The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. Cancer Res.,  2010, 70(16), 6548-6555.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0475] [PMID:  20663905] 
[152] 
Slupianek, A.; Gurdek, E.; Koptyra, M.; Nowicki, M.O.; Siddiqui, K.M.; Groden, J.; Skorski, T. BLM helicase is activated in BCR/ABL leukemia cells to modulate responses to cisplatin. Oncogene,  2005, 24(24), 3914-3922.
[http://dx.doi.org/10.1038/sj.onc.1208545] [PMID:  15750625] 
[153] 
Mo, D.; Fang, H.; Niu, K.; Liu, J.; Wu, M.; Li, S.; Zhu, T.; Aleskandarany, M.A.; Arora, A.; Lobo, D.N.; Madhusudan, S.; Balajee, A.S.; Chi, Z.; Zhao, Y. Human helicase RecQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway. Cancer Res.,  2016, 76(10), 3057-3066.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2361] [PMID:  27013200] 
Cite As
Anti-Cancer Agents in Medicinal Chemistry

RecQ Family Helicases in Replication Fork Remodeling and Repair: Opening New Avenues towards the Identification of Potential Targets for Cancer Chemotherapy

Abstract

Graphical Abstract
