Title | XLF and H2AX function in series to promote replication fork stability. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chen B-R, Quinet A, Byrum AK, Jackson J, Berti M, Thangavel S, Bredemeyer AL, Hindi I, Mosammaparast N, Tyler JK, Vindigni A, Sleckman BP |
Journal | J Cell Biol |
Volume | 218 |
Issue | 7 |
Pagination | 2113-2123 |
Date Published | 2019 07 01 |
ISSN | 1540-8140 |
Keywords | Animals, 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. |
DOI | 10.1083/jcb.201808134 |
Alternate Journal | J Cell Biol |
PubMed ID | 31123184 |
PubMed Central ID | PMC6605786 |
Grant List | R01 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.