Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress.

TitlePolyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress.
Publication TypeJournal Article
Year of Publication2012
AuthorsCiccia, A, Nimonkar, AV, Hu, Y, Hajdu, I, Achar, YJagadheesh, Izhar, L, Petit, SA, Adamson, B, Yoon, JC, Kowalczykowski, SC, Livingston, DM, Haracska, L, Elledge, SJ
JournalMol Cell
Volume47
Issue3
Pagination396-409
Date Published2012 Aug 10
ISSN1097-4164
KeywordsAmino Acid Sequence, Cell Line, Tumor, DNA Damage, DNA Helicases, DNA Replication, Genomic Instability, Green Fluorescent Proteins, Humans, Molecular Sequence Data, Osteosarcoma, Polyubiquitin, Proliferating Cell Nuclear Antigen, Protein Binding, Recombination, Genetic, Sister Chromatid Exchange, Stress, Physiological, Ubiquitination
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.

DOI10.1016/j.molcel.2012.05.024
Alternate JournalMol. Cell
PubMed ID22704558
PubMed Central IDPMC3613862
Grant ListP01 CA080111 / CA / NCI NIH HHS / United States
55005612 / / Howard Hughes Medical Institute / United States
R37 GM062653 / GM / NIGMS NIH HHS / United States
R01 GM044664 / GM / NIGMS NIH HHS / United States
R01 GM062653 / GM / NIGMS NIH HHS / United States
GM62653 / GM / NIGMS NIH HHS / United States
R37 GM044664 / GM / NIGMS NIH HHS / United States