*2.1.3 Mismatch repair (MMR)*

 The mismatched nucleotides in the DNA can result from polymerase misincorporation errors, recombination between imperfectly matched sequences, chemical or physical damage to nucleotides, and deamination of 5-methylcytosine (5mC) mostly during replication. MMR pathway consists of four major heterodimeric complexes, MutL homolog (MutL)α, MutLβ, MutS homolog (MutS)α, and MutSβ. MutLα involves MLH1 and PMS2, whereas MutLβ consist of MLH1 and PMS1. Meanwhile, MutSα consists of MSH2 and MSH6, and MutSβ is constituted by MSH2 and MSH3. Thus, MutSα complex recognizes single mispaired bases, whereas MutSβ detects mispaired runs of 3–6 bases. MutSα or MutSβ recruits MutLα or MutLβ and forms a tetrameric complex that serves as a base for the recruitment of excision and repair machinery [56]. MMR removes mispaired bases preventing mutations [57], and defects in this pathway are strongly associated with a substantial destabilization of microsatellites, which are tandemly repeated sequences (from 1 to 6 bp), highly polymorphic, interspersed in the genome, and susceptible to slippage during replication [58]. Previously, a decline in MMR function and efficiency correlation with age

was observed [59, 60], especially in microsatellite sequences [61] where age-related methylation of the MLH1 [62, 63] and MSH2 [64] promoters could be associated to microsatellite instability (MSI). Interestingly, MLH1 shores showed a decrease in methylation with increasing age [65]. Shores are regions of the genome around CpG islands with lower GC content and with the ability to control gene expression.
