DNA double-strand breaks in telophase lead to coalescence between segregated sister chromatid loci

Jessel Ayra-Plasencia,Félix Machín

doi:10.1038/s41467-019-10742-8

Jessel Ayra-Plasencia, Félix Machín

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https://doi.org/10.1038/s41467-019-10742-8

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DNA double strand breaks (DSBs) pose a high risk for genome integrity. Cells repair DSBs through homologous recombination (HR) when a sister chromatid is available. HR is upregulated by the cycling dependent kinase (CDK) despite the paradox of telophase, where CDK is high but a sister chromatid is not nearby. Here we study in the budding yeast the response to DSBs in telophase, and find they activate the DNA damage checkpoint (DDC), leading to a telophase-to-G1 delay. Outstandingly, we observe a partial reversion of sister chromatid segregation, which includes approximation of segregated material, de novo formation of anaphase bridges, and coalescence between sister loci. We finally show that DSBs promote a massive change in the dynamics of telophase microtubules (MTs), together with dephosphorylation and relocalization of kinesin-5 Cin8. We propose that chromosome segregation is not irreversible and that DSB repair using the sister chromatid is possible in telophase.

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We address this paradox by studying the cell response to double strand breaks (DSBs) in telophase
The results shown above question the irreversible nature of chromosome segregation, at least in budding yeast
We provide mechanistic bases for this regression (Fig. 8): (i) weakening of the elongated spindle, likely through dephosphorylation-dependent relocalization of the bipolar kinesin-5 Cin[8], which allows sister loci to get closer; (ii) local decondesation of chromatin, which favours passage through the bud neck; and (iii) acceleration of loci movement, which increases the probability of closer sister loci to coalesce

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Introduction

We address this paradox by studying the cell response to DSBs in telophase. We find that such response resembles in many ways what is seen in S/G2, including the activation of the DNA damage checkpoint (DDC), which leads to a delay in the telophase-G1 transition in this case. We observe that the segregation of sister chromatids is partly reverted and that sister loci can coalesce after generation of DSBs. We further show that this regression phenotype mechanistically depends on the DDC, as well as the kinesin-5 microtubule motor protein Cin[8]. We conclude that chromosome segregation can be a reversible process

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