Fig. 3

Alterations of DNA damage repair. DDR generally consists of HRR, NHEJ, Replication fork, BER, NER, MMR, TLS, and FA. The repair of DSBs occurs predominately through NHEJ repair pathway in conjunction with HRR pathway. NHEJ are initiated by binding of Ku70–Ku80 heterodimer to DNA ends. The subsequent recruitment and autophosphorylation of DNA-PKcs bring the DNA ends together and allow their ligation by XRCC4–LIG4. MRN complex (MRE11-RAD50-NBS1), an important repair factor of HRR, detects the DNA damage firstly and activates downstream signaling. Besides, it exerts nuclease activity to resect DNA end, guiding to HRR. Further, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Decreased DYNLL1 restores HR-mediated double-strand DNA breaks repair. Replication fork protection is a modality independent of DSBs, which contributes to gene stabilization, leading to chemoresistance and PARPi resistance. Additionally, down-expression of 53BP1 protein is another mechanism to restore DNA end resection. Shieldin (SHLD1, SHLD2, SHLD3 and REV7), as an effector complex of 53BP1, can mediate 53BP1 dependent DNA repair in a BRCA-independent manner. The kinases ATR and ATM have crucial roles in DDR pathway, such as maintaining replication fork stability and regulating CHK1 and CHK2.CHK1 can activate the G2/M inhibiting kinase WEE1 to maintain genomic integrity. Some miRNAs were shown to regulate the expression of components involved in HRR, NHEJ, Replication fork protection, TLS, and FA, but the interaction between miRNA and BER/ NER/ MMR lack sufficient evidence. (SLC, solute carrier superfamily; GST, Glutathione transferase; MT, Metallothionein)