DNA mismatch repair protein

Function

DNA mismatch repair proteins are key players in genomic stability by signalling mismatches occurring during DNA replication and recombination^[1] .

MutS is prokaryotic and recognizes base-base mismatches and small insertion/deletion mispairs^[2] .
MutL enhances recognition of mismatches^[3]
MutH is the eukaryotic homolog of MutS. See also DNA Repair
MLH1, MLH3, PMS1, PMS2 are the human homologs of MutL^[4]

Disease

Mutations in DNA mismatch repair proteins cause hereditary colorectal cancer and loss of these proteins cause significant fraction of sporadic cancers^[5].

Structural highlights

MutS is composed of several domains: N-terminal mismatch-recognition domain; connector domain; core domain; clamp domain; ATPase domain; helix-turn-helix domain. The complex between E. coli MutS and DNA in the scanning mode shows the straight DNA strand clamped between the two MutS monomers and held by the (residues 1-115) and the (residues 444-503)^[6]. In the 3D structure of the mismatch-bound MutS, the DNA strand is kinked by 60 degrees.

3D structures of DNA mismatch repair protein

DNA mismatch repair protein 3D structures

ReferencesReferences

↑ Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008 Jan;18(1):85-98. doi: 10.1038/cr.2007.115. PMID:18157157 doi:http://dx.doi.org/10.1038/cr.2007.115
↑ Lamers MH, Perrakis A, Enzlin JH, Winterwerp HH, de Wind N, Sixma TK. The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch. Nature. 2000 Oct 12;407(6805):711-7. PMID:11048711 doi:10.1038/35037523
↑ Guarne A, Ramon-Maiques S, Wolff EM, Ghirlando R, Hu X, Miller JH, Yang W. Structure of the MutL C-terminal domain: a model of intact MutL and its roles in mismatch repair. EMBO J. 2004 Oct 27;23(21):4134-45. Epub 2004 Oct 7. PMID:15470502
↑ Ellison AR, Lofing J, Bitter GA. Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. doi: 10.1093/nar/gkh855. Print, 2004. PMID:15475387 doi:http://dx.doi.org/10.1093/nar/gkh855
↑ Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008 Jul-Aug;129(7-8):391-407. doi: 10.1016/j.mad.2008.02.012., Epub 2008 Mar 4. PMID:18406444 doi:http://dx.doi.org/10.1016/j.mad.2008.02.012
↑ Fernandez-Leiro R, Bhairosing-Kok D, Kunetsky V, Laffeber C, Winterwerp HH, Groothuizen F, Fish A, Lebbink JHG, Friedhoff P, Sixma TK, Lamers MH. The selection process of licensing a DNA mismatch for repair. Nat Struct Mol Biol. 2021 Apr;28(4):373-381. doi: 10.1038/s41594-021-00577-7., Epub 2021 Apr 5. PMID:33820992 doi:http://dx.doi.org/10.1038/s41594-021-00577-7

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Michal Harel, Alexander Berchansky

[1] Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008 Jan;18(1):85-98. doi: 10.1038/cr.2007.115. PMID:18157157 doi:http://dx.doi.org/10.1038/cr.2007.115

[2] Lamers MH, Perrakis A, Enzlin JH, Winterwerp HH, de Wind N, Sixma TK. The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch. Nature. 2000 Oct 12;407(6805):711-7. PMID:11048711 doi:10.1038/35037523

[3] Guarne A, Ramon-Maiques S, Wolff EM, Ghirlando R, Hu X, Miller JH, Yang W. Structure of the MutL C-terminal domain: a model of intact MutL and its roles in mismatch repair. EMBO J. 2004 Oct 27;23(21):4134-45. Epub 2004 Oct 7. PMID:15470502

[4] Ellison AR, Lofing J, Bitter GA. Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. doi: 10.1093/nar/gkh855. Print, 2004. PMID:15475387 doi:http://dx.doi.org/10.1093/nar/gkh855

[5] Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008 Jul-Aug;129(7-8):391-407. doi: 10.1016/j.mad.2008.02.012., Epub 2008 Mar 4. PMID:18406444 doi:http://dx.doi.org/10.1016/j.mad.2008.02.012

[6] Fernandez-Leiro R, Bhairosing-Kok D, Kunetsky V, Laffeber C, Winterwerp HH, Groothuizen F, Fish A, Lebbink JHG, Friedhoff P, Sixma TK, Lamers MH. The selection process of licensing a DNA mismatch for repair. Nat Struct Mol Biol. 2021 Apr;28(4):373-381. doi: 10.1038/s41594-021-00577-7., Epub 2021 Apr 5. PMID:33820992 doi:http://dx.doi.org/10.1038/s41594-021-00577-7

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