Figure 3.

Biological roles for TMEJ. a) Recue of blocked HR by TMEJ. TMEJ generates deletion scars, but can restore chromosome integrity when resected ends are unable to form a presynaptic filament (block 1; e.g. due to BRCA2 deficiency) or unable to perform strand exchange (block 2; e.g. due to BRCA1 deficiency). When non-cross over (NCO) resolution of HR by synthesis dependent strand annealing (SDSA) is blocked (block 3), TMEJ suppresses Holliday junction (HJ) resolvase-mediated crossovers (CO) between maternal and paternal chromosomes and associated loss of heterozygosity (LOH), or alternatively sister chromatid exchanges (SCE). c) Protein-adducted ends block NHEJ, and can be resolved by TMEJ after removal by Mre11 or strand displacement synthesis. d) Stalling of the replication fork at protein adducts and secondary structures, including G quadruplexes (G4), activates Ataxia Telangiectasia related kinase (ATR) dependent pathways including fork reversal, or can result in daughter strand gaps that break (potentially after cell division, in the next S phase), and are repaired by TMEJ. d) V(D)J recombination intermediates are retained in a complex with RAG1 and RAG2 proteins (red circle) during the G1 phase of the cell cycle, which blocks access of ends to TMEJ. Intermediates not repaired in NHEJ deficient cells are resolved by TMEJ after entry of cells into S phase after S-phase dependent destruction of RAG proteins and activation of resection.