Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2010 Jan 13

PMID 20065033

Citations 89

Authors

Saravanabhavan Thangavel

Ramiro Mendoza-Maldonado

Erika Tissino

Julia M Sidorova

Jinhu Yin

Weidong Wang

Raymond J Monnat Jr

Arturo Falaschi

Alessandro Vindigni

Affiliations

Soon will be listed here.

Abstract

Cellular and biochemical studies support a role for all five human RecQ helicases in DNA replication; however, their specific functions during this process are unclear. Here we investigate the in vivo association of the five human RecQ helicases with three well-characterized human replication origins. We show that only RECQ1 (also called RECQL or RECQL1) and RECQ4 (also called RECQL4) associate with replication origins in a cell cycle-regulated fashion in unperturbed cells. RECQ4 is recruited to origins at late G(1), after ORC and MCM complex assembly, while RECQ1 and additional RECQ4 are loaded at origins at the onset of S phase, when licensed origins begin firing. Both proteins are lost from origins after DNA replication initiation, indicating either disassembly or tracking with the newly formed replisome. Nascent-origin DNA synthesis and the frequency of origin firing are reduced after RECQ1 depletion and, to a greater extent, after RECQ4 depletion. Depletion of RECQ1, though not that of RECQ4, also suppresses replication fork rates in otherwise unperturbed cells. These results indicate that RECQ1 and RECQ4 are integral components of the human replication complex and play distinct roles in DNA replication initiation and replication fork progression in vivo.

Citing Articles

RECQ4-MUS81 interaction contributes to telomere maintenance with implications to Rothmund-Thomson syndrome.

Ashraf R, Polasek-Sedlackova H, Marini V, Prochazkova J, Hasanova Z, Zacpalova M Nat Commun. 2025; 16(1):1302.

PMID: 39900600 PMC: 11791078. DOI: 10.1038/s41467-025-56518-1.

RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining.

Hussain M, Khadka P, Pekhale K, Kulikowicz T, Gray S, May A Exp Mol Med. 2025; 57(1):264-280.

PMID: 39870799 PMC: 11799438. DOI: 10.1038/s12276-024-01383-z.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mackay H, Stone H, Ronson G, Ellis K, Lanz A, Aghabi Y Nat Commun. 2024; 15(1):8102.

PMID: 39284827 PMC: 11405836. DOI: 10.1038/s41467-024-52250-4.

RECQL4 is not critical for firing of human DNA replication origins.

Padayachy L, Ntallis S, Halazonetis T Sci Rep. 2024; 14(1):7708.

PMID: 38565932 PMC: 10987555. DOI: 10.1038/s41598-024-58404-0.

The structural mechanism of dimeric DONSON in replicative helicase activation.

Cvetkovic M, Passaretti P, Butryn A, Reynolds-Winczura A, Kingsley G, Skagia A Mol Cell. 2023; 83(22):4017-4031.e9.

PMID: 37820732 PMC: 7616792. DOI: 10.1016/j.molcel.2023.09.029.

References

Masumoto H, Muramatsu S, Kamimura Y, Araki H . S-Cdk-dependent phosphorylation of Sld2 essential for chromosomal DNA replication in budding yeast. Nature. 2002; 415(6872):651-5. DOI: 10.1038/nature713. View

Bachrati C, Hickson I . RecQ helicases: guardian angels of the DNA replication fork. Chromosoma. 2008; 117(3):219-33. DOI: 10.1007/s00412-007-0142-4. View

Abdurashidova G, Danailov M, Ochem A, Triolo G, Djeliova V, Radulescu S . Localization of proteins bound to a replication origin of human DNA along the cell cycle. EMBO J. 2003; 22(16):4294-303. PMC: 175794. DOI: 10.1093/emboj/cdg404. View

Epner E, Forrester W, Groudine M . Asynchronous DNA replication within the human beta-globin gene locus. Proc Natl Acad Sci U S A. 1988; 85(21):8081-5. PMC: 282358. DOI: 10.1073/pnas.85.21.8081. View

Diviacco S, Norio P, Zentilin L, Menzo S, Clementi M, Biamonti G . A novel procedure for quantitative polymerase chain reaction by coamplification of competitive templates. Gene. 1992; 122(2):313-20. DOI: 10.1016/0378-1119(92)90220-j. View

Davalos A, Kaminker P, Hansen R, Campisi J . ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation. Cell Cycle. 2004; 3(12):1579-86. DOI: 10.4161/cc.3.12.1286. View

Sidorova J, Li N, Folch A, Monnat Jr R . The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle. 2008; 7(6):796-807. PMC: 4362724. DOI: 10.4161/cc.7.6.5566. View

Wang H, Elledge S . DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1999; 96(7):3824-9. PMC: 22379. DOI: 10.1073/pnas.96.7.3824. View

Davies S, North P, Hickson I . Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat Struct Mol Biol. 2007; 14(7):677-9. DOI: 10.1038/nsmb1267. View

10.

von Kobbe C, Bohr V . A nucleolar targeting sequence in the Werner syndrome protein resides within residues 949-1092. J Cell Sci. 2002; 115(Pt 20):3901-7. DOI: 10.1242/jcs.00076. View

11.

Wu L, Davies S, Levitt N, Hickson I . Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. J Biol Chem. 2001; 276(22):19375-81. DOI: 10.1074/jbc.M009471200. View

12.

Yin J, Kwon Y, Varshavsky A, Wang W . RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Hum Mol Genet. 2004; 13(20):2421-30. DOI: 10.1093/hmg/ddh269. View

13.

Sage J, Miller A, Perez-Mancera P, Wysocki J, Jacks T . Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003; 424(6945):223-8. DOI: 10.1038/nature01764. View

14.

Paolinelli R, Mendoza-Maldonado R, Cereseto A, Giacca M . Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 2009; 16(4):412-20. DOI: 10.1038/nsmb.1583. View

15.

Tsang W, Wang L, Chen Z, Sanchez I, Dynlacht B . SCAPER, a novel cyclin A-interacting protein that regulates cell cycle progression. J Cell Biol. 2007; 178(4):621-33. PMC: 2064469. DOI: 10.1083/jcb.200701166. View

16.

Xu D, Guo R, Sobeck A, Bachrati C, Yang J, Enomoto T . RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 2008; 22(20):2843-55. PMC: 2569887. DOI: 10.1101/gad.1708608. View

17.

Sakamoto S, Nishikawa K, Heo S, Goto M, Furuichi Y, Shimamoto A . Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51. Genes Cells. 2001; 6(5):421-30. DOI: 10.1046/j.1365-2443.2001.00433.x. View

18.

Jin W, Liu H, Zhang Y, Otta S, Plon S, Wang L . Sensitivity of RECQL4-deficient fibroblasts from Rothmund-Thomson syndrome patients to genotoxic agents. Hum Genet. 2008; 123(6):643-53. PMC: 2585174. DOI: 10.1007/s00439-008-0518-4. View

19.

Bischof O, Kim S, Irving J, Beresten S, Ellis N, Campisi J . Regulation and localization of the Bloom syndrome protein in response to DNA damage. J Cell Biol. 2001; 153(2):367-80. PMC: 2169463. DOI: 10.1083/jcb.153.2.367. View

20.

Chu W, Hickson I . RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer. 2009; 9(9):644-54. DOI: 10.1038/nrc2682. View