Pai Chen-Chun, Deegan Rachel S, Subramanian Lakxmi, Gal Csenge, Sarkar Sovan, Blaikley Elizabeth J, Walker Carol, Hulme Lydia, Bernhard Eric, Codlin Sandra, Bähler Jürg, Allshire Robin, Whitehall Simon, Humphrey Timothy C
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, The University of Edinburgh, Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK.
Nat Commun. 2014 Jun 9;5:4091. doi: 10.1038/ncomms5091.
DNA double-strand break (DSB) repair is a highly regulated process performed predominantly by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. How these pathways are coordinated in the context of chromatin is unclear. Here we uncover a role for histone H3K36 modification in regulating DSB repair pathway choice in fission yeast. We find Set2-dependent H3K36 methylation reduces chromatin accessibility, reduces resection and promotes NHEJ, while antagonistic Gcn5-dependent H3K36 acetylation increases chromatin accessibility, increases resection and promotes HR. Accordingly, loss of Set2 increases H3K36Ac, chromatin accessibility and resection, while Gcn5 loss results in the opposite phenotypes following DSB induction. Further, H3K36 modification is cell cycle regulated with Set2-dependent H3K36 methylation peaking in G1 when NHEJ occurs, while Gcn5-dependent H3K36 acetylation peaks in S/G2 when HR prevails. These findings support an H3K36 chromatin switch in regulating DSB repair pathway choice.
DNA双链断裂（DSB）修复是一个受到高度调控的过程，主要由非同源末端连接（NHEJ）或同源重组（HR）途径来执行。目前尚不清楚这些途径在染色质环境中是如何协调的。在这里，我们揭示了组蛋白H3K36修饰在调控裂殖酵母中DSB修复途径选择方面的作用。我们发现，Set2依赖的H3K36甲基化降低了染色质的可及性，减少了切除并促进了NHEJ，而具有拮抗作用的Gcn5依赖的H3K36乙酰化则增加了染色质可及性，增加了切除并促进了HR。因此，Set2缺失会增加H3K36Ac、染色质可及性和切除，而在DSB诱导后，Gcn5缺失会导致相反的表型。此外，H3K36修饰受细胞周期调控，Set2依赖的H3K36甲基化在发生NHEJ的G1期达到峰值，而Gcn5依赖的H3K36乙酰化在HR占主导的S/G2期达到峰值。这些发现支持了H3K36染色质开关在调控DSB修复途径选择中的作用。
