BLM and the FANC Proteins Collaborate in a Common Pathway in Response to Stalled Replication Forks

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2004 Jul 17

PMID 15257300

Citations 60

Authors

Pietro Pichierri

Annapaola Franchitto

Filippo Rosselli

Affiliations

Soon will be listed here.

Abstract

Fanconi anaemia (FA) and Bloom syndrome (BS) are autosomal recessive diseases characterised by chromosome fragility and cancer proneness. Here, we report that BLM and the FA pathway are activated in response to both crosslinked DNA and replication fork stall. We provide evidence that BLM and FANCD2 colocalise and co-immunoprecipitate following treatment with either DNA crosslinkers or agents inducing replication arrest. We also find that the FA core complex is necessary for BLM phosphorylation and assembly in nuclear foci in response to crosslinked DNA. Moreover, we show that knock-down of the MRE11 complex, whose function is also under the control of the FA core complex, enhances cellular and chromosomal sensitivity to DNA interstrand crosslinks in BS cells. These findings suggest the existence of a functional link between BLM and the FA pathway and that BLM and the MRE11 complex are in two separated branches of a pathway resulting in S-phase checkpoint activation, chromosome integrity and cell survival in response to crosslinked DNA.

Citing Articles

Replication stress as a driver of cellular senescence and aging.

Herr L, Schaffer E, Fuchs K, Datta A, Brosh Jr R Commun Biol. 2024; 7(1):616.

PMID: 38777831 PMC: 11111458. DOI: 10.1038/s42003-024-06263-w.

A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation.

Cohen S, Guenole A, Lazar I, Marnef A, Clouaire T, Vernekar D Nat Commun. 2022; 13(1):2012.

PMID: 35440629 PMC: 9019021. DOI: 10.1038/s41467-022-29629-2.

USP37 regulates DNA damage response through stabilizing and deubiquitinating BLM.

Wu C, Chang Y, Chen J, Su Y, Li L, Chen Y Nucleic Acids Res. 2021; 49(19):11224-11240.

PMID: 34606619 PMC: 8565321. DOI: 10.1093/nar/gkab842.

PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair.

Ninou A, Lehto J, Chioureas D, Stigsdotter H, Schelzig K, Akerlund E Cancers (Basel). 2021; 13(14).

PMID: 34298817 PMC: 8306909. DOI: 10.3390/cancers13143604.

EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart.

Hambarde S, Tsai C, Pandita R, Bacolla A, Maitra A, Charaka V Mol Cell. 2021; 81(14):2989-3006.e9.

PMID: 34197737 PMC: 8720176. DOI: 10.1016/j.molcel.2021.05.027.

References

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

Lukas C, Falck J, Bartkova J, Bartek J, Lukas J . Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nat Cell Biol. 2003; 5(3):255-60. DOI: 10.1038/ncb945. View

Wang Y, Cortez D, Yazdi P, NEFF N, Elledge S, Qin J . BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000; 14(8):927-39. PMC: 316544. View

Taniguchi T, Garcia-Higuera I, Xu B, Andreassen P, Gregory R, Kim S . Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell. 2002; 109(4):459-72. DOI: 10.1016/s0092-8674(02)00747-x. View

Osborn A, Elledge S, Zou L . Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol. 2002; 12(11):509-16. DOI: 10.1016/s0962-8924(02)02380-2. View

Hyrien O . Mechanisms and consequences of replication fork arrest. Biochimie. 2000; 82(1):5-17. DOI: 10.1016/s0300-9084(00)00344-8. View

Waisfisz Q, de Winter J, Kruyt F, de Groot J, van der Weel L, Dijkmans L . A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad Sci U S A. 1999; 96(18):10320-5. PMC: 17886. DOI: 10.1073/pnas.96.18.10320. View

van Brabant A, Stan R, Ellis N . DNA helicases, genomic instability, and human genetic disease. Annu Rev Genomics Hum Genet. 2001; 1:409-59. DOI: 10.1146/annurev.genom.1.1.409. View

DAndrea A, Grompe M . The Fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003; 3(1):23-34. DOI: 10.1038/nrc970. View

10.

Heinrich M, Hoatlin M, Zigler A, Silvey K, Bakke A, Keeble W . DNA cross-linker-induced G2/M arrest in group C Fanconi anemia lymphoblasts reflects normal checkpoint function. Blood. 1998; 91(1):275-87. View

11.

Rothfuss A, Grompe M . Repair kinetics of genomic interstrand DNA cross-links: evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Mol Cell Biol. 2003; 24(1):123-34. PMC: 303365. DOI: 10.1128/MCB.24.1.123-134.2004. View

12.

Ababou M, Dutertre S, Lecluse Y, Onclercq R, Chatton B, Amor-Gueret M . ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation. Oncogene. 2001; 19(52):5955-63. DOI: 10.1038/sj.onc.1204003. View

13.

Taniguchi T, Garcia-Higuera I, Andreassen P, Gregory R, Grompe M, DAndrea A . S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood. 2002; 100(7):2414-20. DOI: 10.1182/blood-2002-01-0278. View

14.

Rosselli F, Briot D, Pichierri P . The Fanconi anemia pathway and the DNA interstrand cross-links repair. Biochimie. 2004; 85(11):1175-84. DOI: 10.1016/j.biochi.2003.11.002. View

15.

Ababou M, Dumaire V, Lecluse Y, Amor-Gueret M . Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition. Oncogene. 2002; 21(13):2079-88. DOI: 10.1038/sj.onc.1205246. View

16.

Mirzoeva O, Petrini J . DNA replication-dependent nuclear dynamics of the Mre11 complex. Mol Cancer Res. 2003; 1(3):207-18. View

17.

Nakanishi K, Taniguchi T, Ranganathan V, New H, Moreau L, Stotsky M . Interaction of FANCD2 and NBS1 in the DNA damage response. Nat Cell Biol. 2002; 4(12):913-20. DOI: 10.1038/ncb879. View

18.

Pichierri P, Averbeck D, Rosselli F . DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein. Hum Mol Genet. 2002; 11(21):2531-46. DOI: 10.1093/hmg/11.21.2531. View

19.

Hickson I, Davies S, Li J, Levitt N, Mohaghegh P, North P . Role of the Bloom's syndrome helicase in maintenance of genome stability. Biochem Soc Trans. 2001; 29(Pt 2):201-4. DOI: 10.1042/0300-5127:0290201. View

20.

Hickson I . RecQ helicases: caretakers of the genome. Nat Rev Cancer. 2003; 3(3):169-78. DOI: 10.1038/nrc1012. View