Sin3a is essential for the genome integrity and viability of pluripotent cells

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 is required for proliferation and survival of pluripotent embryonic cells. ► Sin3a-/- mouse ICM cells are eliminated by p53-independent apoptosis. ► Sin3a is a critical regulator of the unusual pluripotent embryonic cell cycle. ► Sin3a prevents or repairs DSBs that arise in ES cells, perhaps during replication. ► The Sin3a interactome provides insights into function Sin3a in ES cells.