Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Dev Biol. 2012 Mar 1;363(1):62-73. doi: 10.1016/j.ydbio.2011.12.019. Epub 2011 Dec 20.
The Sin3a/HDAC co-repressor complex is a critical regulator of transcription networks that govern cell cycle control and apoptosis throughout development. Previous studies have identified Sin3a as essential for embryonic development around the time of implantation, during which the epiblast cell cycle is uniquely structured to achieve very rapid divisions with little tolerance of DNA damage. This study investigates the specific requirement for Sin3a in the early mouse embryo and shows that embryos lacking Sin3a suffer unresolved DNA damage and acute p53-independent apoptosis specifically in the E3.5-4.5 epiblast. Surprisingly, Myc and E2F targets in Sin3a-null ICMs are downregulated, suggesting a central but non-canonical role for Sin3a in regulating the pluripotent embryonic cell cycle. ES cells deleted for Sin3a mount a DNA damage response indicative of unresolved double-strand breaks, profoundly arrest at G2, and undergo apoptosis. These results indicate that Sin3a protects the genomic integrity of pluripotent embryonic cells and governs their unusual cell cycle.
Sin3a/HDAC 共抑制复合物是转录网络的关键调节因子，该网络控制着细胞周期的控制和凋亡在整个发育过程中的作用。之前的研究已经确定 Sin3a 在胚胎植入前后的胚胎发育中是必不可少的，在此期间，外胚层细胞周期的结构独特，能够实现非常快速的分裂，对 DNA 损伤的容忍度很低。本研究调查了 Sin3a 在早期小鼠胚胎中的特定需求，并表明缺乏 Sin3a 的胚胎在 E3.5-4.5 外胚层中会出现未解决的 DNA 损伤和急性 p53 非依赖性凋亡。令人惊讶的是，Sin3a 缺失的 ICMs 中的 Myc 和 E2F 靶基因下调，表明 Sin3a 在调节多能胚胎细胞周期中具有核心但非经典的作用。缺失 Sin3a 的 ES 细胞会引发表明未解决的双链断裂的 DNA 损伤反应，严重地在 G2 期停滞，并发生凋亡。这些结果表明 Sin3a 保护多能胚胎细胞的基因组完整性，并控制其异常的细胞周期。
