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- Title
γH2A binds Brc1 to maintain genome integrity during S-phase.
- Authors
Williams, Jessica S.; Williams, R. Scott; Dovey, Claire L.; Guenther, Grant; Tainer, John A.; Russell, Paul
- Abstract
ATMTel1 and ATRRad3 checkpoint kinases phosphorylate the C-terminus of histone H2AX (H2A in yeasts) in chromatin flanking DNA damage, establishing a recruitment platform for checkpoint and repair proteins. Phospho-H2A/X (γH2A/X)-binding proteins at double-strand breaks (DSBs) have been characterized, but those required for replication stress responses are unknown. Here, we present genetic, biochemical, small angle X-ray scattering (SAXS), and X-ray structural studies of the Schizosaccharomyces pombe Brc1, a 6-BRCT-domain protein that is structurally related to Saccharomyces cerevisiae Rtt107 and mammalian PTIP. Brc1 binds γH2A to form spontaneous and DNA damage-induced nuclear foci. Spontaneous Brc1 foci colocalize with ribosomal DNA repeats, a region prone to fork pausing and genomic instability, whereas DNA damage-induced Brc1 foci colocalize with DSB response factors. γH2A binding is critical for Brc1 function. The 1.45 Å resolution crystal structure of Brc1–γH2A complex shows how variable BRCT insertion loops sculpt tandem-BRCT phosphoprotein-binding pockets to facilitate unique phosphoprotein-interaction specificities, and unveils an acidic DNA-mimicking Brc1 surface. From these results, Brc1 docking to γH2A emerges as a critical chromatin-specific response to replication-associated DNA damage.
- Publication
EMBO Journal, 2010, Vol 29, Issue 6, p1136
- ISSN
0261-4189
- Publication type
Academic Journal
- DOI
10.1038/emboj.2009.413