Cohesin still drives homologous recombination repair of DNA double-strand breaks in late mitosis

  1. Jessel Ayra-Plasencia
  2. Lorraine Symington
  3. Félix Machín

  • Curated by eLife

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    eLife assessment

    This study presents evidence that suggests that the coalescence of sister chromatids induced by global double-strand DNA breaks (DSBs) during late mitosis is mediated by cohesin SMC3. These findings are valuable for studying the mechanism of eukaryotic cells to repair DNA during late mitosis. Although the discrete DSB induction system in budding yeast is sound, the strength of evidence is incomplete and could be buttressed to better support the major claims and to represent a clear advance with respect to the authors' previous contributions to this field.

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Abstract

The cohesin complex maintains sister chromatid cohesion from S phase to anaphase onset. Cohesin also plays roles in chromosome structure and DNA repair. At anaphase onset, the cohesin subunit Scc1 is cleaved to allow segregation in an orderly manner, although some residual cohesin subunits remain to maintain chromosome structure. Efficient DNA double-strand break (DSB) repair by homologous recombination (HR) with the sister chromatid also depends on cohesin. Here, we have tested whether residual cohesin is important during DSB repair in anaphase/telophase (late mitosis). Using the well-established MAT switching system, we first show that HR is molecularly functional in late mitosis, and then show that cohesin is required for its efficiency. During DSBs in late mitosis, the segregated sister loci get closer and have episodes of coalescence, which may favour repair by HR. Here, we also show that these cytological phenotypes also depend on cohesin. Finally, full-length Scc1 returns after DSBs in late mitosis, suggesting that de novo widespread cohesin complexes can support these retrograde behaviours.

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  1. Version published to 10.7554/elife.92706.1 on eLife
  2. Version published to 10.7554/elife.92706 on eLife
  3. eLife

    eLife assessment

    This study presents evidence that suggests that the coalescence of sister chromatids induced by global double-strand DNA breaks (DSBs) during late mitosis is mediated by cohesin SMC3. These findings are valuable for studying the mechanism of eukaryotic cells to repair DNA during late mitosis. Although the discrete DSB induction system in budding yeast is sound, the strength of evidence is incomplete and could be buttressed to better support the major claims and to represent a clear advance with respect to the authors' previous contributions to this field.

  4. eLife

    Reviewer #1 (Public Review):

    Summary:
    The cohesin complex maintains sister chromatid cohesion from S phase to anaphase. Beyond that, DSBs trigger cohesin recruitment and post-replication cohesion at both damage sites and globally, which was originally reported in 2004. In their recent study, Ayra-Plasencia et al reported in telophase, DSBs are repaired via HR with re-coalesced sister chromatids (Ayra-Plasencia & Machín, 2019). In this study, they show that HR occurs in a Smc3-dependent way in late mitosis.

    Strengths:
    The authors take great advantage of the yeast system, they check the DSB processing and repair of a single DSB generated by HO endonuclease, which cuts the MAT locus in chromosome III. In combination with cell synchronization, they detect the HR repair during G2/M or late mitosis. and the cohesin subunit SMC3 is critical for this repair. Beyond that, full-length Scc1 protein can be recovered upon DSBs.

    Weaknesses:
    These new results basically support their proposal although with a very limited molecular mechanistic progression, especially compared with their recent work.

  5. eLife

    Reviewer #2 (Public Review):

    Summary:
    The manuscript "Cohesin still drives homologous recombination repair of DNA double-strand breaks in late mitosis" by Ayra-Plasencia et al. investigates regulations of HR repair in conditional cdc15 mutants, which arrests the cell cycle in late anaphase/telophase. Using a non-competitive MAT switching system of S. cerevisiae, they show that a DSB in telophase-arrested cells elicits a delayed DNA damage checkpoint response and resection. Using a degron allele of SMC3 they show that MATa-to-alpha switching requires cohesin in this context. The presence of a DSB in telophase-arrested cells leads to an increase in the kleisin subunit Scc1 and a partial rejoining of sister chromatids after they have separated in a subset of cells.

    Strengths:
    The experiments presented are well-controlled. The induction systems are clean and well thought-out.

    Weaknesses:
    The manuscript is very preliminary, and I have reservations about its physiological relevance. I also have reservations regarding the usage of MAT to make the point that inter-sister repair can occur in late mitosis.

  6. Version published to 10.1101/2023.09.08.556828v1 on bioRxiv