Figure 2.

Major double-strand break (DSB) repair pathways in human cells. DSBs in G1 of the cell cycle are primarily repaired by non-homologous end joining (NHEJ) (Top). This pathway is initiated by the Ku heterodimer, which recognizes broken DNA. NHEJ leads to repair with minimal alteration to the original sequence. DSBs in S/G2 phases are subjected to resection leading to stretches of single-stranded DNA. Resected DSBs are substrates for homologous recombination (HR) with a critical role of Rad51 leading to an accurate repair synthesis. When HR is defective (for example when BRCA genes are mutated), an alternative pathway named Pol theta-mediated end-joining (TMEJ) can act as a back-up repair pathway. Polθ promotes the synapsis of the opposing ends, identifies internal microhomologies, which can be annealed, and performs a repair DNA synthesis with poor processivity and frequent aborted synthesis, resulting in a high rate of mutations. Single-strand annealing (SSA) is a HR sub-pathway in mammalian cells with the essential role of RAD52 DNA-binding protein. SSA is an error-prone repair leading to large deletions between the homologous repeats.