The mismatch repair (MMR) system detects non-Watson – Crick base pairs as well as the defects, appearing in course of DNA replication, and helps to eliminate them by catalyzing the excision of the defect-containing region of daughter DNA and its error-free resynthesis. Thus, MMR remarkably improves the fidelity of replication. After separation, both strands contain non-repairable damages and the mismatches may generate DNA mutation in 50 % of cell progeny after next replication. MMR dysfunction causes surge of mutation rate, abnormal recombination, and cancer in humans and animals. Therefore, the main MMR efficiency parameter is mismatch correction before the next replication cycle. Mismatch detection is made by the MSH2 protein, which forms a heterodimer with either MSH6 or MSH3 (Mut S), depending on the damage (MSH6 is needed for the amendment of single base mispairs, whereas both MSH3 and MSH6 can correct IDLs). A heterodimer of MLH1 and PMS2 (Mut L) controls the interaction between the mismatch-detecting complex of proteins and other proteins essential for MMR, including exonuclease 1, helicase, nuclear antigen of proliferating cells, single-stranded DNA-binding protein and DNA polymerases δ and ε. MLH1 can form a heterodimer with two additional proteins – MLH3 and PMS1. PMS2 is required for the correction of single based mismatches, and PMS2 and MLH3 contribute to the correction of IDLs. The Nobel Prize in Chemistry 2015 was awarded for the studies of DNA repair, i.a. MMR.
MMR, post-replication DNA repair , Nobel Prize in Chemistry , excision of bases, MutS α or MutS β, MutLα, PCNA, DNA-polymerase δ, DNA-ligase I
1. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (1996). hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl. Acad. Sci. U.S.A., (93), 13629-13634.
2. Arana ME, Kunkel TA (2010). Mutator phenotypes due to DNA replication infidelity. Semin. Cancer Biol., (20), 304-311.
3. Cannavo E, Marra G, Sabates-Bellver J, Menigatti M, Lipkin SM, Fischer F, Cejka P, Jiricny J (2005). Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair. Cancer Res., (65), 10759-10766.
4. Drummond JT, Li G-M, Longley MJ, Modrich P (1995). Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science, (268), 1909-1912.
5. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993). The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell, (75), 1027-1038.
6. Genschel J, Bazemore LR, Modrich P (2002). Human exonuclease I is required for 5′ and 3′ mismatch repair. J. Biol. Chem., (277), 13302-13311.
7. Genschel J, Littman SJ, Drummond JT (1998). Isolation of MutSβ from Human Cells and Comparison of the Mismatch Repair Specificities of MutSβ and MutSα. J. Biol Chem., (273), 19895-19901.
8. Goellner EM, Putnam CD, Kolodner RD (2015). Exonuclease 1-dependent and independent mismatch repair. DNA Repair, (32), 24-32.
9. Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R (1999). hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol. Cell, (3), 255-261.
10. Gu Y, Parker A, Wilson TM, Bai H, Chang D-Y, Lu A-L (2002). Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins humanMutS homolog 2/human MutS homolog 6. J. Biol. Chem., (277), 11135-11142.
11. Harrington JM, Kolodner RD (2007). Saccharomyces cerevisiae Msh2-Msh3 acts in repair of base-base mispairs. Mol. Cell. Biol., (27), 6546-6554.
12. Iyer RR, Pluciennik A, Genschel J (2010). MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta. J. Biol. Chem., (285), 11730-11739.
13. Jiricny J. (2013). Postreplicative mismatch repair. Cold Spring Harb. Perspect Biol. URL: http://cshperspectives. cshlp.org/content/5/4/a012633.
14. Jiricny J (1998). Replication errors: cha(lle)nging the genome. EMBO J., 17 (22), 6427-6436.
15. Jiricny J (2006). The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol., (7), 335-346.
16. Kadyrov FA, Dzantiev L, Constantin N, Modrich P (2006). Endonucleolytic function of MutLa in human mismatch repair. Cell, (126), 297-308.
17. Kunkel TA, Erie DA (2005). DNA mismatch repair. Annu. Rev. Biochem., (74), 681-710.
18. Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M (1993). Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell, (75), 1215-1225.
19. Li GM, Modrich P (1995). Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc. Natl. Acad. Sci. U.S.A., (92), 1950-1954.
20. Li GM (2008). Mechanisms and functions of DNA mismatch repair. Cell Res., (18), 85-98.
21. Longley MJ, Pierce AJ, Modrich P (1997). DNA polymerase delta is required for human mismatch repair in vitro. J. Biol. Chem., (272), 10917-10921.
22. Modrich P (2006). Mechanisms in eukaryotic mismatch repair. J. Biol. Chem., (281), 30305-30309.
23. Mugesh G (2015). Nobel Prize in Chemistry for DNA repair. Current Science, 109 (9), 1533-1536.
24. Natrajan G, Lamers MH, Enzlin JH, Winterwerp HHK, Perrakis A, Sixma TK (2003). Structures of Escherichia coli DNA mismatch repair enzyme MutS in complex with different mismatches: A common recognition mode for diverse substrates. Nucleic Acids Res., (31), 4814- 4821.
25. Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM (1994). Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature, (371), 75-80.
26. Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes MD, Arrigo A, Truong O, Hsuan JJ, Jiricny J (1995). GTBP, a 160-kilodalton protein essential for mismatchbinding activity in human cells. Science, (268), 1912-1914.
27. Palombo F, Iaccarino I, Nakajima E, Ikejima M, Shimada T, Jiricny J (1996). hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr. Biol., (6), 1181-1184.
28. Pena-Diaz J, Jiricny J (2012). Mammalian mismatch repair: Error-free or error-prone. Trends Biochem. Sci., (37), 206-214.
29. Pluciennik A, Dzantiev L, Lyer RR (2010). PCNA function in the activation and strand direction of MutLalpha endonuclease in mismatch repair. Proc. Natl. Acad. Sci. U.S.A., (107), 16066-16071.
30. Pluciennik A, Modrich P (2007). Protein roadblocks and helix discontinuities are barriers to the initiation of mismatch repair. Proc. Natl. Acad. Sci. U.S.A., (104), 12709-12713.
31. Sachadyn P (2010). Conservation and diversity of MutS proteins. Mutat. Res., (694), 20-30.
32. Surtees JA, Alani E (2006). Mismatch repair factor MSH2-MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination. J. Molec. Biol., (360), 523-536.
