Multi-BRCT scaffolds use distinct strategies to support genome maintenance

Abstract

Genome maintenance requires coordinated actions of diverse DNA metabolism processes. Scaffolding proteins, such as those containing multiple BRCT domains, can influence these processes by collaborating with numerous partners. The best-studied examples of multi-BRCT scaffolds are the budding yeast Dpb11 and its homologues in other organisms, which regulate DNA replication, repair, and damage checkpoints. Recent studies have shed light on another group of multi-BRCT scaffolds, including Rtt107 in budding yeast and related proteins in other organisms. These proteins also influence several DNA metabolism pathways, though they use strategies unlike those employed by the Dpb11 family of proteins. Yet, at the same time, these 2 classes of multi-BRCT proteins can collaborate under specific situations. This review summarizes recent advances in our understanding of how these multi-BRCT proteins function in distinct manners and how they collaborate, with a focus on Dpb11 and Rtt107.

Brc1 Promotes the Focal Accumulation and SUMO Ligase Activity of Smc5-Smc6 during Replication Stress

“…Our data showing that Nse5-Nse6 and Brc1 together support Smc5-Smc6 focal accumulation, chromatin association, and SUMO ligase activity now provide an explanation for the importance of Nse5-Nse6 in genome stability. Brc1 is structurally related to budding yeast Rtt107 and human PTIP in terms of their content of 6 BRCT domains, although PTIP has a different linker arrangement than the yeast proteins (35). These three BRCT domain-containing proteins share the ability to bind gamma-H2A that is formed by the master checkpoint kinases at DNA lesions (2,36,37).…”

“…These three BRCT domain-containing proteins share the ability to bind gamma-H2A that is formed by the master checkpoint kinases at DNA lesions (2,36,37). However, Brc1, Rtt107, and PTIP appear to bind functionally distinct cofactors (1,35,38,39), which likely accounts for the markedly different synthetic genetic interaction profiles of Rtt107 and Brc1 (40). Therefore, despite their common involvement in the replication stress response (2,3,38,39), Brc1, Rtt107, and PTIP appeared to function in different pathways.…”

“…During replicative stress or following the induction of DNA double-strand breaks (DSBs), Rtt107 was found to interact with the budding yeast Smc5-Smc6 complex (38,41). Although fission yeast Smc5-Smc6 does not accumulate at DSBs, there is a clear parallel between the interaction of Brc1 and Rtt107 with Smc5-Smc6 in response to collapsed replication forks (35,38,42).…”

Multi-BRCT Domain Protein Brc1 Links Rhp18/Rad18 and γH2A To Maintain Genome Stability during S Phase

“…1A) (16). This domain organization is shared with Saccharomyces cerevisiae Rtt107, which is an important genome protection protein (17)(18)(19)(20)(21). The mammalian genome protection protein PTIP also has six BRCT domains, although its linker region is located between domains 2 and 3 (18,22).…”

“…This domain organization is shared with Saccharomyces cerevisiae Rtt107, which is an important genome protection protein (17)(18)(19)(20)(21). The mammalian genome protection protein PTIP also has six BRCT domains, although its linker region is located between domains 2 and 3 (18,22). Brc1 was first identified in S. pombe as an allele-specific high-copy-number suppressor of the hypomorphic smc6-74 allele, which impairs the function of the essential Smc5/6 structural maintenance of chromosomes complex (23).…”