BMI-1 regulates DNA end resection and homologous recombination repair

BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.

Automated summary

BMI-1 is a crucial regulator of gene transcriptional silencing during development. Its role in the DNA damage response has recently gained attention, but the exact mechanism remains unclear. This study establishes that BMI-1 plays an important role in the repair of DNA double-strand breaks through homologous recombination by promoting DNA end resection. Mechanistically, BMI-1 facilitates the recruitment of CtIP, allowing accumulation of RPA and RAD51 at DNA damage sites. Additionally, H2A ubiquitylation at K119 has been found to promote end resection.