Brc1 links replication stress response and centromere function

Si Young Lee

doi:10.4161/cc.24900

2014-11-03

Si Young Lee

Paul Russell *

DOI：10.4161/cc.24900

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摘要

En 中文

protection of genome integrity 1 depends on the coordinated activities of DNA replication, DNA repair, chromatin assembly and chromosome segregation mechanisms. DNA lesions are detected by the master checkpoint kinases ATM (Tell) and ATR (Rad3/Mec1), which phosphorylate multiple substrates, including a C-terminal SQ motif in histone H2A or H2AX. The 6-BRCT domain protein Bra, which is required for efficient recovery from replication fork arrest and collapse in fission yeast, binds phospho-histone H2A (gamma H2A)-coated chromatin at stalled and damaged replication forks. We recently found that Brcl co-localizes with -yH2A that appears in pericentromeric heterochromatin during S-phase. Our studies indicate that Brcl contributes to the maintenance of pericentromeric heterochromatin, which is required for efficient chromosome segregation during mitosis. Here, we review these studies and present additional results that establish the functional requirements for the N-terminal BRCT domains of Brcl in the replication stress response and resistance to the microtubule destabilizing drug thiabendazole (TBZ). We also identify the nuclear localization signal (NLS) in Brcl, which closely abuts the C-terminal pair of BRCT domains that form the gamma H2A-binding pocket. This compact arrangement of localization domains may be a shared feature of other gamma H2A-binding proteins, including Rtt107, PTIP and Mdc1.

Keyword:

DNA damage response

replication stress

heterochromatin

centromere

BRCT domain

mitosis

nuclear localization signal