CRUK-MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6B, UK.
Cell Rep. 2017 Sep 12;20(11):2693-2705. doi: 10.1016/j.celrep.2017.08.058.
Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast.
组蛋白 H3 赖氨酸 36 甲基化通过 SETD2 肿瘤抑制因子进行染色质修饰，在维持基因组稳定性方面发挥着关键作用。在这里，我们描述了 SET2 依赖性 H3K36 甲基化在促进有丝分裂酵母中 MluI 细胞周期盒（MCB）结合因子（MBF）-复合物依赖性转录中的作用，这种作用有助于 DNA 复制以及对复制应激和 DNA 损伤的转录反应。Set2 的缺失导致 MBF 依赖性核核苷酸还原酶（RNR）表达减少，脱氧核苷三磷酸（dNTP）合成减少，复制起点点火改变，以及有丝分裂检查点依赖性 S 期延迟。因此，在没有 Set2 的情况下，通过增加 dNTP 合成来抑制延长的 S 期。此外，这些 MBF 基因启动子上的 H3K36 被二甲基化和三甲基化，Set2 的缺失导致对遗传毒性应激的 MBF 结合和转录减少。总之，这些发现为 H3K36 甲基化如何促进 DNA 复制和促进有丝分裂酵母中的遗传毒性应激反应提供了新的见解。
