Structure of C-terminal Tandem BRCT Repeats of Rtt107 Protein Reveals Critical Role in Interaction with Phosphorylated Histone H2A during DNA Damage Repair

Li, Xinxin; Liu, Kaixian; Li, Fudong; Wang, Juncheng; Huang, Hongda; Wu, Jihui; Shi, Yunyu

doi:10.1074/jbc.m111.311860

Cited by 48 publications

(56 citation statements)

References 47 publications

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“…[33][34][35][36] As seen for Brc1, both Rtt107 and PTIP bind γH2A(X) through their C-terminal BRCT domains. 18,37,38 To address the functional significance of the N-terminal BRCT domains of Brc1 for survival of replication stress and exposure to TBZ, we performed mutational analyses of conserved residues in BRCT domains 2, 3 and 4. Of the five mutants tested, brc1-TH148-9SG, brc1-R268K and brc1-HYP307-9GFG caused sensitivity to the replication stress agents camptothecin (CPT) and hydroxyurea (HU), which primarily act by causing replication fork collapse and arrest, respectively (Fig.…”

Section: Functional Analyses Of the N-terminal Brct Domains Of Brc1 Imentioning

confidence: 99%

Brc1 links replication stress response and centromere function

Lee¹,

Russell²

2013

Cell Cycle

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Protection of genome integrity 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 (Tel1) and ATR (Rad3/ Mec1), which phosphorylate multiple substrates, including a C-terminal SQ motif in histone H2A or H2AX. The 6-BRCT domain protein Brc1, which is required for efficient recovery from replication fork arrest and collapse in fission yeast, binds phospho-histone H2A (γH2A)-coated chromatin at stalled and damaged replication forks. We recently found that Brc1 co-localizes with γH2A that appears in pericentromeric heterochromatin during S-phase. Our studies indicate that Brc1 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 Brc1 in the replication stress response and resistance to the microtubule destabilizing drug thiabendazole (TBZ). We also identify the nuclear localization signal (NLS) in Brc1, which closely abuts the C-terminal pair of BRCT domains that form the γH2A-binding pocket. This compact arrangement of localization domains may be a shared feature of other γH2A-binding proteins, including Rtt107, PTIP and Mdc1.

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Section: Functional Analyses Of the N-terminal Brct Domains Of Brc1 Imentioning

confidence: 99%

Brc1 links replication stress response and centromere function

Lee¹,

Russell²

2013

Cell Cycle

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“…Conversely, single BRCT domains have diverse functions, and their mechanisms cannot be extrapolated from one protein to another due to low sequence identity. Furthermore, their specific functions remain elusive because many BRCT domains, like the one found in Dbf4, require additional structural elements to become functional (12,16,17). The BRCT domain of Dbf4 is immediately preceded by an ␣-helix that stabilizes the domain, and thus, it has been previously referred to as HBRCT (12,18).…”

mentioning

confidence: 99%

A Novel Non-canonical Forkhead-associated (FHA) Domain-binding Interface Mediates the Interaction between Rad53 and Dbf4 Proteins

Matthews

Selvaratnam

Jones

et al. 2014

Journal of Biological Chemistry

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Background:The interaction between the checkpoint kinase Rad53 and Dbf4 is critical to suppress late origin firing and to stabilize stalled forks during replication stress. Results: The FHA1 domain of Rad53 interacts with the BRCT domain of Dbf4 through a novel non-canonical interface. Conclusion: FHA domains gain specificity by engaging multiple binding interfaces. Significance: Understanding how FHA domains interact with their binding partners is key to elucidate how they relay information along signaling pathways.

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“…[56][57][58] Recent studies demonstrate that the BRCT5-6 of all 3 proteins adopt a similar structure and directly bind to gH2A, a phosphorylated form of H2A generated by Mec1 (hATR) or its paralog Tel1 (hATM). [59][60][61][62][63] The interaction between gH2A and BRCT5-6 helps recruit Rtt107 and Brc1 to sites where gH2A is enriched, such as DNA double strand breaks (DSBs) and regions behind replication forks (Fig. 2).…”

Section: Rtt107-like Proteins Interact With Histones and Distinct Setmentioning

confidence: 99%

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

2016

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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.

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Structure of C-terminal Tandem BRCT Repeats of Rtt107 Protein Reveals Critical Role in Interaction with Phosphorylated Histone H2A during DNA Damage Repair

Cited by 48 publications

References 47 publications

Brc1 links replication stress response and centromere function

Brc1 links replication stress response and centromere function

A Novel Non-canonical Forkhead-associated (FHA) Domain-binding Interface Mediates the Interaction between Rad53 and Dbf4 Proteins

Multi-BRCT scaffolds use distinct strategies to support genome maintenance

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