SP6 safeguards human multipotent trophoblasts from DNA damage-induced ageing by shaping DNA-PK complex

The placenta can be threatened by DNA damage caused by genotoxic events. However, how placental trophoblasts coordinate cell type-restricted mechanisms in response to DNA damage and how they maintain genome stability remains elusive. We previously reported that the transcription factor SP6 regulates the fate of human cytotrophoblasts (CTs) and trophoblast stem cells (TSCs). Here, we demonstrate that SP6 interacts with DNA-PKcs in CTs and TSCs to shape the phosphorylation pattern of this kinase for DNA damage repair (DDR), a role that is independent of its transcriptional activity. Lack of SP6 leads to the inactivation of DNA-PKcs, defects in DNA-PK complex assembly and DDR, and eventually cell senescence. Moreover, pharmaceutically or genetically targeting OTUB1-SP6 regulatory axis, which controls the dynamic turnover of cellular SP6 during DDR, can reset the susceptibility of CTs or TSCs to genotoxic stress-induced DNA damage. Taken together, these findings identify a CT- or TSC-specific DDR mechanism, and we propose a potential druggable target for mitigating DNA damage and cell senescence-related human placental diseases.