A tentative model for TMEJ of breaks induced at replication fork barriers. DNA lesions from endogenous sources—with increased frequency in the absence of functional TLS—causes replication fork blocks, leading to double-stranded breaks. The broken ends are repaired by pol theta-mediated end joining (TMEJ), which is stimulated by minimal priming of 1 base pair, explaining deletions with single nucleotide homology (left). Iterative cycles of priming, extending, and dissociation will result in deletions with templated insertions (right). In pol theta-deficient cells, DNA breaks resulting from replication fork stalling are differently processed, eventually leading to larger size deletions.
