Postreplicative Recruitment of Cohesin to Double-Strand Breaks Is Required for DNA Repair

Department of Cell and Molecular Biology, Karolinska Institute, Berzelius väg 35, 171 77 Stockholm, Sweden.
Molecular Cell (Impact Factor: 14.02). 01/2005; 16(6):1003-15. DOI: 10.1016/j.molcel.2004.11.026
Source: PubMed


Chromosome stability depends on accurate chromosome segregation and efficient DNA double-strand break (DSB) repair. Sister chromatid cohesion, established during S phase by the protein complex cohesin, is central to both processes. In the absence of cohesion, chromosomes missegregate and G2-phase DSB repair fails. Here, we demonstrate that G2-phase repair also requires the presence of cohesin at the damage site. Cohesin components are shown to be recruited to extended chromosome regions surrounding DNA breaks induced during G2. We find that in the absence of functional cohesin-loading proteins (Scc2/Scc4), the accumulation of cohesin at DSBs is abolished and repair is defective, even though sister chromatids are connected by S phase generated cohesion. Evidence is also provided that DSB induction elicits establishment of sister chromatid cohesion in G2, implicating that damage-recruited cohesin facilitates DNA repair by tethering chromatids.

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Available from: Camilla Sjögren, Dec 14, 2013
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    • " so induces detachment of early S - phase kinetochore – microtubule attachments essential for cohesin - independent segregation ( Figure 2A ) . CPT inhibits topoisomerase I , which induces single - strand nicks that can become double - strand DNA breaks ( DSBs ) during replication in S phase . Because cohesin / cohesion play a role in DSB repair ( Ström et al . , 2004 ; Unal et al . , 2004 ) , CPT lethality is likely due to a combi - nation of reduced repair of DSBs and DNA - damage checkpoint – in - duced cell - cycle delays , increasing the likelihood of loss kineto - chore – microtubule attachments formed in S phase . We wanted to identify mutations that restore cohesion to eco1∆ wpl1∆ cells . We "
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    ABSTRACT: Cohesin complex mediates cohesion between sister chromatids, which promotes high fidelity chromosome segregation. Eco1p acetylates the cohesin subunit Smc3p during S phase to establish cohesion. The current model posits that this Eco1p mediated acetylation promotes establishment by abrogating the ability of Wpl1p to destabilize cohesin binding to chromosomes. Here, we present data from budding yeast that is incompatible with this Wpl1p-centric model. Two independent in vivo assays show that a wpl1∆ fails to suppress cohesion defects of eco1∆ cells. Moreover, a wpl1∆ also fails to suppress cohesion defects engendered by blocking just the essential Eco1p acetylation sites on Smc3p (K112,K113). Thus, removing WPL1 inhibition is insufficient for generating cohesion without ECO1 activity. To elucidate how ECO1 promotes cohesion, we conducted a genetic screen and identified a cohesion activator mutation in the SMC3 head domain (D1189H). Smc3-D1189H partially restores cohesion in eco1∆ wpl1∆ or eco1 mutant cells but robustly restores cohesion in cells blocked for Smc3p K112 K113 acetylation. These data support two important conclusions. First, acetylation of K112 K113 region by Eco1p promotes cohesion establishment by altering Smc3p head function independent of its ability to antagonize Wpl1p. Second, Eco1p targets other than Smc3p K112 K113 are necessary for efficient establishment.
    Molecular Biology of the Cell 11/2014; 26(1). DOI:10.1091/mbc.E14-08-1268 · 4.47 Impact Factor
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    • "In addition to its function in chromosome segregation, cohesin plays important roles in other nuclear processes including the DNA damage response and DNA repair (Kim et al, 2002; Yazdi et al, 2002; Strom et al, 2004; Unal et al, 2004; Watrin & Peters, 2009), chromatin organization and gene regulation. Cohesin facilitates transcriptional termination between convergent genes in yeast (Gullerova & Proudfoot, 2008) and controls the developmentally regulated expression of genes in multiple systems (Rollins et al, 2004; Horsfield et al, 2007; Landeira et al, 2009; Pauli et al, 2010). "
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    • "Cohesin and condensin also function in DNA repair (Wu and Yu 2012). Cohesin is recruited to sites of DNA DSBs to facilitate HR through sister-chromatid cohesion and to elicit an efficient DNA damage checkpoint response (Kim et al. 2002; Ström et al. 2004; Unal et al. 2004). Condensin is implicated in repair of single- and double-strand breaks and in ribosomal DNA stability (Aono et al. 2002; Heale et al. 2006; Tsang et al. 2007; Wood et al. 2008). "
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