Polyubiquitinated PCNA Recruits the ZRANB3 Translocase to Maintain Genomic Integrity after Replication Stress

Alberto Ciccia, Amitabh Nimonkar, Yiduo Hu, Ildiko Hajdu, Yathish Jagadheesh Achar, Lior Izhar, Sarah A. Petit, Britt Adamson, John C. Yoon, Stephen C Kowalczykowski, David M. Livingston, Lajos Haracska, Stephen J. Elledge

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

Completion of DNA replication after replication stress depends on PCNA, which undergoes monoubiquitination to stimulate direct bypass of DNA lesions by specialized DNA polymerases or is polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Here we report that the ZRANB3 translocase, a SNF2 family member related to the SIOD disorder SMARCAL1 protein, is recruited by polyubiquitinated PCNA to promote fork restart following replication arrest. ZRANB3 depletion in mammalian cells results in an increased frequency of sister chromatid exchange and DNA damage sensitivity after treatment with agents that cause replication stress. Using in vitro biochemical assays, we show that recombinant ZRANB3 remodels DNA structures mimicking stalled replication forks and disassembles recombination intermediates. We therefore propose that ZRANB3 maintains genomic stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events.

Original languageEnglish (US)
Pages (from-to)396-409
Number of pages14
JournalMolecular Cell
Volume47
Issue number3
DOIs
StatePublished - Aug 10 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Ciccia, A., Nimonkar, A., 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. (2012). Polyubiquitinated PCNA Recruits the ZRANB3 Translocase to Maintain Genomic Integrity after Replication Stress. Molecular Cell, 47(3), 396-409. https://doi.org/10.1016/j.molcel.2012.05.024