TY - JOUR
T1 - XLF and H2AX function in series to promote replication fork stability
AU - Chen, Bo Ruei
AU - Quinet, Annabel
AU - Byrum, Andrea K.
AU - Jackson, Jessica
AU - Berti, Matteo
AU - Thangavel, Saravanabhavan
AU - Bredemeyer, Andrea L.
AU - Hindi, Issa
AU - Mosammaparast, Nima
AU - Tyler, Jessica K.
AU - Vindigni, Alessandro
AU - Sleckman, Barry P.
N1 - Funding Information:
A. Vindigni is supported by National Institutes of Health grant R01GM108648 and Department of Defense Award BC151728. B.P. Sleckman is supported by National Institutes of Health grants AI047829 and AI074953. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Chen et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019
Y1 - 2019
N2 - 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, H2ax−/−:Xlf−/− 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.
AB - 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, H2ax−/−:Xlf−/− 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.
UR - http://www.scopus.com/inward/record.url?scp=85069264585&partnerID=8YFLogxK
U2 - 10.1083/jcb.201808134
DO - 10.1083/jcb.201808134
M3 - Article
C2 - 31123184
AN - SCOPUS:85069264585
SN - 0021-9525
VL - 218
SP - 2113
EP - 2123
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 7
ER -