Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery
View/ Open
Author
Murphy, Anar K.
Fitzgerald, Michael
Ro, Teresa
Kim, Jee Hyun
Rabinowitsch, Ariana I.
Schildkraut, Carl L.
Borowiec, James A.
Published Version
https://doi.org/10.1083/jcb.201404111Metadata
Show full item recordCitation
Murphy, Anar K., Michael Fitzgerald, Teresa Ro, Jee Hyun Kim, Ariana I. Rabinowitsch, Dipanjan Chowdhury, Carl L. Schildkraut, and James A. Borowiec. 2014. “Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery.” The Journal of Cell Biology 206 (4): 493-507. doi:10.1083/jcb.201404111. http://dx.doi.org/10.1083/jcb.201404111.Abstract
Phosphorylation of replication protein A (RPA) by Cdk2 and the checkpoint kinase ATR (ATM and Rad3 related) during replication fork stalling stabilizes the replisome, but how these modifications safeguard the fork is not understood. To address this question, we used single-molecule fiber analysis in cells expressing a phosphorylation-defective RPA2 subunit or lacking phosphatase activity toward RPA2. Deregulation of RPA phosphorylation reduced synthesis at forks both during replication stress and recovery from stress. The ability of phosphorylated RPA to stimulate fork recovery is mediated through the PALB2 tumor suppressor protein. RPA phosphorylation increased localization of PALB2 and BRCA2 to RPA-bound nuclear foci in cells experiencing replication stress. Phosphorylated RPA also stimulated recruitment of PALB2 to single-strand deoxyribonucleic acid (DNA) in a cell-free system. Expression of mutant RPA2 or loss of PALB2 expression led to significant DNA damage after replication stress, a defect accentuated by poly-ADP (adenosine diphosphate) ribose polymerase inhibitors. These data demonstrate that phosphorylated RPA recruits repair factors to stalled forks, thereby enhancing fork integrity during replication stress.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137056/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065457
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)