Figure 2 .

Brief description of the DSB repair mechanism in hematopoietic system

In HSCs, DSBs are mainly caused by excessive endogenous replication stress ( e. g., ROS-induced) and DNA-ICL incision or application of exogenous chemotherapeutics ( e. g., ionizing radiation and radiomimetic, compounds). Two major pathways, termed HR and c-NHEJ facilitate DSB repair. HR mainly occurs in the S/G2-phase, where the DSB ends first undergo nucleolytic resection performed by the CtIP-MRN (MRE11-RAD50-NBS1) complex to generate single-strand DNA (ssDNA). The subsequent steps include replication protein A (RPA)-ssDNA nucleofilament formation, RAD51 loading to replace RPA, and strand invasion. The proliferative HSCs mainly use HR to complete DSB repair, which is also true for the repair of the DSBs generated in the FA/BRCA pathway. c-NHEJ repairs DSBs in the G0/G1-phase, where the DNA ends are blocked by Ku70/Ku80/DNA-PKcs and then undergo blunt end ligation by XRCC4-LIG4. It is well known that c-NHEJ is essential for V(D)J rearrangement during lymphocyte development. In addition, c-NHEJ plays the dominant role in DSBs repair for quiescent HSCs, which are in the G0-phase of the cell cycle. HSC, hematopoietic stem cell; ssDNA, single-strand DNA.