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 mismatch binding domain (residues 1-115) and the clamp domain (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
- ↑ 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:https://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:https://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:https://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:https://dx.doi.org/10.1038/s41594-021-00577-7
