Fig. 2

The mechanism of normal MMR system and dMMR/MSI. a The MMR system consists of four major proteins: MLH1, MSH2, MSH6 and PMS2. They work in the form of heterodimers: MLH1 couples with PMS2 (MutLα), and MSH2 couples with MSH6 (MutSα). MutSα recognizes DNA mismatched base errors, creates a sliding clamp around DNA, undergoes an ATP-driven conformational switch and subsequently binds MutLα. The complexes interact with enzymes including DNA polymerase to excise the mismatch and resynthesize DNA. b Germline mutations in MMR genes, epigenetic hypermethylation of MMR gene promotor or biallelic somatic inactivation of MMR genes could lead to loss of MMR protein expression and deficient MMR system. dMMR is likely to cause DNA sequence alterations in microsatellites, and accumulation of which is called MSI. TA-dinucleotide repeats are unstable and expanded in dMMR/MSI cells. These cells are dependent on WRN to maintain genome stability, and avoid TA-dinucleotide repeats cleavage and chromosome shattering