Bmi1 is a major determinant of hematopoietic stem cell (HSC) self-renewal. To date, much of our understanding of Bmi1 function comes from studies linking it to p16ink4a-Rb and p19arf-p53 pathways. However, several observations have raised the possibility that Bmi1 requirement for the maintenance of stem cell self-renewal ability extends far beyond its role in repressing the INK4a/ARF locus. The phenotypical similarities shared between Bmi1 deficiency in mouse and Fanconi Anemia (FA) patients (e.g., congenital aplastic anemia) together with the reported mono-ubiquitin ligase activities of proteins in both complexes and the emerging concept connecting DNA repair to stem cell properties, prompted us to evaluate Bmi1 implication in DNA damage repair. We now report that, like FA cells, Bmi1-deficient HSCs accumulate at G2/M phase of cell cycle. Moreover, Bmi1 is rapidly recruited to DNA damage foci in a PI3 kinase like kinase (PIKK)-dependant manner, in several cell types including hematopoietic stem cells. Upon induction of DNA lesions, Bmi1 interacts with several proteins involved in DNA damage response including γ-H2AX, MDC1, RAP80 and the monoubiquitinated form of FANCD2. We found that Bmi1 depletion did not hinder DNA damage-induced γ-H2AX foci formation and that RNF8-dependent signaling cascade is functional in absence of Bmi1. Furthermore, as observed in FA, loss of Bmi1 is associated with occurrence of spontaneous chromosome breaks and increased sensitivity to clastogenic agents. These chromosome breaks occur although FANCD2 monoubiquitination and loading onto chromatin is preserved. Together this work reveals an unsuspected role for Bmi1 in securing chromosome integrity and connects Polycomb genes to FA repair pathway.
Disclosures: No relevant conflicts of interest to declare.