Chromosome structure due to phospho-mimetic H2A modulates DDR through increased chromatin mobility

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Fernandez, Fabiola, Garcia | Lemos, Brenda | Khalil, Yasmine | Batrin, Renaud | Fabre, Emmanuelle

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In budding yeast and mammals, double strand breaks trigger global chromatin mobility 14 together with the rapid phosphorylation of the histone H2A over an extensive region of the 15 chromatin. To assess the role of H2A phosphorylation in this response to DNA damage, we 16 have constructed strains where H2A has been mutated to the phospho-mimetic H2A-S129E. 17 We show that H2A-S129E mutant increases global motion of chromosomes even in the 18 absence of DNA damage. The intrinsic chromatin mobility of H2A-S129E is not due to 19 checkpoint activation, histone degradation or kinetochore anchoring. Rather, the increased 20 intra-chromosomal distances observed in H2A-S129E mutant are consistent with chromatin 21 structural changes. In this context, the Rad9 53BP1-dependent-checkpoint becomes 22 dispensable. The increase in chromatin dynamics is favorable to NHEJ of a single double-23 strand break but is accompanied by a sharp decrease in inter-chromosomal translocation 24 rates. We propose that changes in chromosomal conformation due to H2A phosphorylation 25 are sufficient to modulate the DDR and maintain genome integrity.

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