Fig. 3

Synthetic lethal pathway: dual pathways. a Dual pathway concept. (i) Pathways 1 and 2 perform the same function to maintain cell survival. (ii) Abnormality (mutation, overexpression, or inhibited) of two or more genes in only one pathway keeps the cell viability. On the contrary, two or more genes on two pathways in abnormal conditions would cause synthetic lethal interactions. b Examples of HR and NHEJ pathways. (i) When DSBs occur in normal cells, BRCA1 is normally expressed and is recruited to sites of breaks, which interacts with 53BP1 to inhibit 53BP1 on the CTIP/MRN complex that promotes end processing to allow HR-mediated repair in S and G2 phases. Whereas in the G0/G1 phase, BRCA1 is silent and 53BP1 is recruited to DSBs to restrain CTIP/MRN activity, which inhibits HR and promotes the classic-NHEJ pathway. (ii) In BRCA-mutated tumors, BRCA1 is not present in S/G2-phase and 53BP1 inhibits CTIP/MRN function, leading to impaired end processing of the breaks, suppression of HR, and promotion of the alternative-NHEJ pathway. In this condition, tumors could still rely on the alternative-NHEJ pathway to repair DSBs and survive. (iii) Use of PARP (a functional gene in the NHEJ pathway) inhibitors will cause synthetic lethality in BRCA-mutated cancers. Star shape of genes represents a mutation; syringe represents inhibitors; viable cells are depicted as ovals; and inviable cells are depicted as random shapes