XLF and H2AX function in series to promote replication fork stability.

TitleXLF and H2AX function in series to promote replication fork stability.
Publication TypeJournal Article
Year of Publication2019
AuthorsChen B-R, Quinet A, Byrum AK, Jackson J, Berti M, Thangavel S, Bredemeyer AL, Hindi I, Mosammaparast N, Tyler JK, Vindigni A, Sleckman BP
JournalJ Cell Biol
Volume218
Issue7
Pagination2113-2123
Date Published2019 07 01
ISSN1540-8140
KeywordsAnimals, Ataxia Telangiectasia Mutated Proteins, Cell Division, DNA Breaks, Double-Stranded, DNA Damage, DNA End-Joining Repair, DNA Repair, DNA Replication, DNA-Binding Proteins, Fibroblasts, Histones, Mice, MRE11 Homologue Protein, Phosphorylation
Abstract

XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF undergoes cell division cycle 7-dependent phosphorylation; associates with the replication factor C complex, a critical component of the replisome; and is found at replication forks. XLF deficiency leads to defects in replication fork progression and an increase in fork reversal. The additional loss of H2AX, which protects DNA ends from resection, leads to a requirement for ATR to prevent an MRE11-dependent loss of newly synthesized DNA and activation of DNA damage response. Moreover, cells exhibit a marked dependence on the ATR kinase for survival. We propose that XLF and H2AX function in series to prevent replication stress induced by the MRE11-dependent resection of regressed arms at reversed replication forks.

DOI10.1083/jcb.201808134
Alternate JournalJ Cell Biol
PubMed ID31123184
PubMed Central IDPMC6605786
Grant ListR01 AI047829 / AI / NIAID NIH HHS / United States
R01 AI074953 / AI / NIAID NIH HHS / United States
R01 CA095641 / CA / NCI NIH HHS / United States
R01 GM108648 / GM / NIGMS NIH HHS / United States
Related Faculty: 
Jessica K. Tyler, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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