FIGURE 3.

Models for ncMMR function in repeat instability. (A) MMR hijacks and stabilizes the hairpins formed at repeats by strand displacement during long-patch BER (LP-BER). This inhibits further processing by other repair mechanisms such as FEN1 dependent flap removal (McMurray, 2008). (B) Nicking in the strand opposite to a hairpin leads to unwinding of the hairpin and resynthesis across resulting in repeat expansion. Processing of the strand containing the hairpin may lead to hairpin removal and repeats contraction (adapted from Gomes-Pereira et al., 2004). (C) Mismatch repair processing of lesions (e.g., oxidative or alkylating damage) may lead to strand degradation and faulty resynthesis resulting in hairpin formation. (D) As in the hijacking model (A), MutSβ stabilization of hairpins formed by polymerase slippage during replication or lack of processing of IDLs results in contraction when the hairpin is located in the template strand or expansions when the hairpin is formed in the newly synthesized strand. (E) Gap filling can lead to hairpin formation by strand displacement during Okazaki fragment processing (Kantartzis et al., 2012; Kim and Mirkin, 2013). (F) Hairpins formed at the template strand can promote MMR processing leading to DSBs. The DSBs formed can be processed by different mechanisms leading to gross chromosomal rearrangements (GCRs) or to repeat length variations (Kim et al., 2008). The models presented here are not mutually exclusive. The asterisk represents a lesion addressed by MMR. The red dotted line indicates MMR-dependent processing including strand degradation and resynthesis steps. Inverted red triangles indicated the position of EXO1 entry site. BIR, break induced replication.