DNA Damage Signaling Recruits the Rtt107-Slx4 Scaffolds via Dpb11 to Mediate Replication Stress Response

Ohouo, Patrice; Oliveira, Francisco Meirelles Bastos de; Almeida, Beatriz S.; Smolka, Marcus B.

doi:10.1016/j.molcel.2010.06.019

Cited by 91 publications

(155 citation statements)

References 26 publications

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“…5B). SMC5/6 is known to be recruited to DSBs by Rtt107 when phosphorylated by the DNA damage checkpoint kinase Mec1 (De Piccoli et al 2006;Ohouo et al 2010;Leung et al 2011;Ullal et al 2011). Consistently, the rtt107Δ strain also compromised relocation of DSBs to the NE in both stages of the cell cycle (Fig.…”

Section: The Soluble Mps3nsupporting

confidence: 55%

PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL

et al. 2016

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High-resolution imaging shows that persistent DNA damage in budding yeast localizes in distinct perinuclear foci for repair. The signals that trigger DNA double-strand break (DSB) relocation or determine their destination are unknown. We show here that DSB relocation to the nuclear envelope depends on SUMOylation mediated by the E3 ligases Siz2 and Mms21. In G1, a polySUMOylation signal deposited coordinately by Mms21 and Siz2 recruits the SUMO targeted ubiquitin ligase Slx5/Slx8 to persistent breaks. Both Slx5 and Slx8 are necessary for damage relocation to nuclear pores. When targeted to an undamaged locus, however, Slx5 alone can mediate relocation in G1-phase cells, bypassing the requirement for polySUMOylation. In contrast, in S-phase cells, monoSUMOylation mediated by the Rtt107-stabilized SMC5/6-Mms21 E3 complex drives DSBs to the SUN domain protein Mps3 in a manner independent of Slx5. Slx5/Slx8 and binding to pores favor repair by ectopic break-induced replication and imprecise end-joining.

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Section: The Soluble Mps3nsupporting

confidence: 55%

PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL

et al. 2016

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“…A component of this function for Brc1 is engagement of the error-prone branch of PRR. In keeping with this model, studies of the Brc1 homolog in budding yeast, Rtt107, have shown it to play a role in replication re-start mediated through its interaction with Slx4 (Ohouo et al, 2010;Roberts et al, 2006). However, Slx4 is a considerably larger protein in S. cerevisiae than in S. pombe, and the region required for the Slx4-Rtt107 interaction is absent in fission yeast (Coulon et al, 2004).…”

Section: Brc1-dependent Genome Stability In S Phase 2761mentioning

confidence: 95%

Brc1-dependent recovery from replication stress

Bass

Murray

O’Connell

2012

Journal of Cell Science

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Summary BRCT-containing protein 1 (Brc1) is a multi-BRCT (BRCA1 carboxyl terminus) domain protein in Schizosaccharomyces pombe that is required for resistance to chronic replicative stress, but whether this reflects a repair or replication defect is unknown and the subject of this study. We show that brc1D cells are significantly delayed in recovery from replication pausing, though this does not activate a DNA damage checkpoint. DNA repair and recombination protein Rad52 is a homologous recombination protein that loads the Rad51 recombinase at resected double-stranded DNA (dsDNA) breaks and is also recruited to stalled replication forks, where it may stabilize structures through its strand annealing activity. Rad52 is required for the viability of brc1D cells, and brc1D cells accumulate Rad52 foci late in S phase that are potentiated by replication stress. However, these foci contain the single-stranded DNA (ssDNA) binding protein RPA, but not Rad51 or cH2A. Further, these foci are not associated with increased recombination between repeated sequences, or increased post-replication repair. Thus, these Rad52 foci do not represent sites of recombination. Following the initiation of DNA replication, the induction of these foci by replication stress is suppressed by defects in origin recognition complex (ORC) function, which is accompanied by loss of viability and severe mitotic defects. This suggests that cells lacking Brc1 undergo an ORC-dependent rescue of replication stress, presumably through the firing of dormant origins, and this generates RPA-coated ssDNA and recruits Rad52. However, as Rad51 is not recruited, and the checkpoint effector kinase Chk1 is not activated, these structures must not contain the unprotected primer ends found at sites of DNA damage that are required for recombination and checkpoint activation. IntroductionDuring DNA replication, cells are extremely vulnerable to DNA damage. This vulnerability is due to both the genomic lesions themselves, but also to the impediment these lesions cause to the completion of replication. Replication forks that encounter sites of DNA damage stall in the face of these lesions, a process that activates the DNA replication checkpoint to help maintain stalled fork stability, halt the cell cycle, and initiate DNA repair. The majority of replication forks are presumed to retain the full complement of replication machinery in a stable conformation at sites of fork stalling until the impeding lesion is repaired. However, some lesions are not readily resolved and so alternative mechanisms for the completion of replication have evolved. These include the collapse of the stalled replication fork and its repair through homologous recombination (HR), bypass of the DNA lesion through the post-replication repair (PRR) pathway, which includes both error-prone and error-free mechanisms, and the completion of replication through the firing of adjacent origins (Branzei and Foiani, 2008;Branzei and Foiani, 2009).PRR mediates lesion bypass through a two-step process. Initia...

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“…This arrangement of domains is conserved in orthologous proteins throughout ascomycete fungi, including Rtt107 protein in Saccharomyces cerevisiae, which is also involved in the cellular responses to replication stress. [30][31][32] The presence of 6-BRCT domains connected by linkers is also found in the PTIP/Swift family of proteins in metazoans, which also appear to function in DNA damage responses. [33][34][35][36] As seen for Brc1, both Rtt107 and PTIP bind γH2A(X) through their C-terminal BRCT domains.…”

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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DNA Damage Signaling Recruits the Rtt107-Slx4 Scaffolds via Dpb11 to Mediate Replication Stress Response

Cited by 91 publications

References 26 publications

PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL

PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL

Brc1-dependent recovery from replication stress

Brc1 links replication stress response and centromere function

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