BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination

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

Research output: Contribution to journalArticle

174 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1210-1222
Number of pages13
JournalEMBO Journal
Volume22
Issue number5
DOIs
StatePublished - Mar 3 2003

Keywords

  • DNA repair
  • Nuclear trafficking
  • RAD51
  • Sister chromatid exchange

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Sengupta, S., Linke, S. P., Pedeux, R., Yang, Q., Farnsworth, J., Garfield, S. H., Valerie, K., Shay, J. W., Ellis, N. A., Wasylyk, B., & Harris, C. C. (2003). BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. EMBO Journal, 22(5), 1210-1222. https://doi.org/10.1093/emboj/cdg114