BLM Helicase-dependent Transport of P53 to Sites of Stalled DNA Replication Forks Modulates Homologous Recombination

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2003 Feb 28

PMID 12606585

Citations 82

Authors

Sagar Sengupta

Steven P Linke

Remy Pedeux

Qin Yang

Julie Farnsworth

Susan H Garfield

Kristoffer Valerie

Jerry W Shay

Nathan A Ellis

Bohdan Wasylyk

Curtis C Harris

Affiliations

Soon will be listed here.

Abstract

Diverse functions, including DNA replication, recombination and repair, occur during S phase of the eukaryotic cell cycle. It has been proposed that p53 and BLM help regulate these functions. We show that p53 and BLM accumulated after hydroxyurea (HU) treatment, and physically associated and co-localized with each other and with RAD51 at sites of stalled DNA replication forks. HU-induced relocalization of BLM to RAD51 foci was p53 independent. However, BLM was required for efficient localization of either wild-type or mutated (Ser15Ala) p53 to these foci and for physical association of p53 with RAD51. Loss of BLM and p53 function synergistically enhanced homologous recombination frequency, indicating that they mediated the process by complementary pathways. Loss of p53 further enhanced the rate of spontaneous sister chromatid exchange (SCE) in Bloom syndrome (BS) cells, but not in their BLM-corrected counterpart, indicating that involvement of p53 in regulating spontaneous SCE is BLM dependent. These results indicate that p53 and BLM functionally interact during resolution of stalled DNA replication forks and provide insight into the mechanism of genomic fidelity maintenance by these nuclear proteins.

Citing Articles

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References

Susse S, Janz C, Janus F, Deppert W, Wiesmuller L . Role of heteroduplex joints in the functional interactions between human Rad51 and wild-type p53. Oncogene. 2000; 19(39):4500-12. DOI: 10.1038/sj.onc.1203809. View

Wang W, Seki M, Narita Y, Sonoda E, Takeda S, Yamada K . Possible association of BLM in decreasing DNA double strand breaks during DNA replication. EMBO J. 2000; 19(13):3428-35. PMC: 313960. DOI: 10.1093/emboj/19.13.3428. View

Slebos R, Taylor J . A novel host cell reactivation assay to assess homologous recombination capacity in human cancer cell lines. Biochem Biophys Res Commun. 2001; 281(1):212-9. DOI: 10.1006/bbrc.2001.4335. View

Gottifredi V, Shieh S, Taya Y, Prives C . p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc Natl Acad Sci U S A. 2001; 98(3):1036-41. PMC: 14704. DOI: 10.1073/pnas.98.3.1036. View

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

Bean L, Stark G . Phosphorylation of serines 15 and 37 is necessary for efficient accumulation of p53 following irradiation with UV. Oncogene. 2001; 20(9):1076-84. DOI: 10.1038/sj.onc.1204204. View

Hoeijmakers J . Genome maintenance mechanisms for preventing cancer. Nature. 2001; 411(6835):366-74. DOI: 10.1038/35077232. View

Appella E, Anderson C . Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem. 2001; 268(10):2764-72. DOI: 10.1046/j.1432-1327.2001.02225.x. View

Gatei M, Zhou B, Hobson K, Scott S, Young D, Khanna K . Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. J Biol Chem. 2001; 276(20):17276-80. DOI: 10.1074/jbc.M011681200. View

10.

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

11.

Wang X, Tseng A, Ellis N, Spillare E, Linke S, Robles A . Functional interaction of p53 and BLM DNA helicase in apoptosis. J Biol Chem. 2001; 276(35):32948-55. DOI: 10.1074/jbc.M103298200. View

12.

Sengupta S, Wasylyk B . Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. Genes Dev. 2001; 15(18):2367-80. PMC: 312780. DOI: 10.1101/gad.202201. View

13.

Lambert S, Lopez B . Role of RAD51 in sister-chromatid exchanges in mammalian cells. Oncogene. 2001; 20(45):6627-31. DOI: 10.1038/sj.onc.1204813. View

14.

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

15.

Raderschall E, Stout K, Freier S, Suckow V, Schweiger S, Haaf T . Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res. 2002; 62(1):219-25. View

16.

Saintigny Y, Lopez B . Homologous recombination induced by replication inhibition, is stimulated by expression of mutant p53. Oncogene. 2002; 21(3):488-92. DOI: 10.1038/sj.onc.1205040. View

17.

Bunz F, Fauth C, Speicher M, Dutriaux A, Sedivy J, Kinzler K . Targeted inactivation of p53 in human cells does not result in aneuploidy. Cancer Res. 2002; 62(4):1129-33. View

18.

Franchitto A, Pichierri P . Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. J Cell Biol. 2002; 157(1):19-30. PMC: 2173275. DOI: 10.1083/jcb.200110009. View

19.

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

20.

Langland G, Elliott J, Li Y, Creaney J, Dixon K, Groden J . The BLM helicase is necessary for normal DNA double-strand break repair. Cancer Res. 2002; 62(10):2766-70. View