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31  structures 3895  species 2  interactions 5404  sequences 69  architectures

Family: DNA_mis_repair (PF01119)

Summary: DNA mismatch repair protein, C-terminal domain

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This is the Wikipedia entry entitled "DNA mismatch repair". More...

DNA mismatch repair Edit Wikipedia article

Diagram of DNA mismatch repair pathways. The first column depicts mismatch repair in eukaryotes, while the second depicts repair in most bacteria. The third column shows mistmatch repair, to be specific in E. coli.

DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.[1][2]

Mismatch repair is strand-specific. During DNA synthesis the newly synthesised (daughter) strand will commonly include errors. In order to begin repair, the mismatch repair machinery distinguishes the newly synthesised strand from the template (parental). In gram-negative bacteria, transient hemimethylation distinguishes the strands (the parental is methylated and daughter is not). However, in other prokaryotes and eukaryotes, the exact mechanism is not clear. It is suspected that, in eukaryotes, newly synthesized lagging-strand DNA transiently contains nicks (before being sealed by DNA ligase) and provides a signal that directs mismatch proofreading systems to the appropriate strand. This implies that these nicks must be present in the leading strand, and evidence for this has recently been found.[3] Recent work[4] has shown that nicks are sites for RFC-dependent loading of the replication sliding clamp PCNA, in an orientation-specific manner, such that one face of the donut-shape protein is juxtaposed toward the 3'-OH end at the nick. Oriented PCNA then directs the action of the MutLalpha endonuclease to one strand in the presence of a mismatch and MutSalpha or MutSbeta.

Any mutational event that disrupts the superhelical structure of DNA carries with it the potential to compromise the genetic stability of a cell. The fact that the damage detection and repair systems are as complex as the replication machinery itself highlights the importance evolution has attached to DNA fidelity.

Examples of mismatched bases include a G/T or A/C pairing (see DNA repair). Mismatches are commonly due to tautomerization of bases during DNA replication. The damage is repaired by recognition of the deformity caused by the mismatch, determining the template and non-template strand, and excising the wrongly incorporated base and replacing it with the correct nucleotide. The removal process involves more than just the mismatched nucleotide itself. A few or up to thousands of base pairs of the newly synthesized DNA strand can be removed.

Mismatch repair proteins

DNA mismatch repair protein, C-terminal domain
PDB 1h7u EBI.jpg
hpms2-atpgs
Identifiers
Symbol DNA_mis_repair
Pfam PF01119
Pfam clan CL0329
InterPro IPR013507
PROSITE PDOC00057
SCOP 1bkn
SUPERFAMILY 1bkn

Mismatch repair is a highly conserved process from prokaryotes to eukaryotes. The first evidence for mismatch repair was obtained from S. pneumoniae (the hexA and hexB genes). Subsequent work on E. coli has identified a number of genes that, when mutationally inactivated, cause hypermutable strains. The gene products are, therefore, called the "Mut" proteins, and are the major active components of the mismatch repair system. Three of these proteins are essential in detecting the mismatch and directing repair machinery to it: MutS, MutH and MutL (MutS is a homologue of HexA and MutL of HexB).

MutS forms a dimer (MutS2) that recognises the mismatched base on the daughter strand and binds the mutated DNA. MutH binds at hemimethylated sites along the daughter DNA, but its action is latent, being activated only upon contact by a MutL dimer (MutL2), which binds the MutS-DNA complex and acts as a mediator between MutS2 and MutH, activating the latter. The DNA is looped out to search for the nearest d(GATC) methylation site to the mismatch, which could be up to 1 kb away. Upon activation by the MutS-DNA complex, MutH nicks the daughter strand near the hemimethylated site. MutL recruits UvrD helicase (DNA Helicase II) to separate the two strands with a specific 3' to 5' polarity. The entire MutSHL complex then slides along the DNA in the direction of the mismatch, liberating the strand to be excised as it goes. An exonuclease trails the complex and digests the ss-DNA tail. The exonuclease recruited is dependent on which side of the mismatch MutH incises the strand – 5' or 3'. If the nick made by MutH is on the 5' end of the mismatch, either RecJ or ExoVII (both 5' to 3' exonucleases) is used. If, however, the nick is on the 3' end of the mismatch, ExoI (a 3' to 5' enzyme) is used.

The entire process ends past the mismatch site - i.e., both the site itself and its surrounding nucleotides are fully excised. The single-strand gap created by the exonuclease can then be repaired by DNA Polymerase III (assisted by single-strand-binding protein), which uses the other strand as a template, and finally sealed by DNA ligase. DNA methylase then rapidly methylates the daughter strand.

MutS homologs

When bound, the MutS2 dimer bends the DNA helix and shields approximately 20 base pairs. It has weak ATPase activity, and binding of ATP leads to the formation of tertiary structures on the surface of the molecule. The crystal structure of MutS reveals that it is exceptionally asymmetric, and, while its active conformation is a dimer, only one of the two halves interacts with the mismatch site.

In eukaryotes, MutS homologs form two major heterodimers: Msh2/Msh6 (MutSα) and Msh2/Msh3 (MutSβ). The MutSα pathway is involved primarily in base substitution and small-loop mismatch repair. The MutSβ pathway is also involved in small-loop repair, in addition to large-loop (~10 nucleotide loops) repair. However, MutSβ does not repair base substitutions.

MutL homologs

MutL also has weak ATPase activity (it uses ATP for purposes of movement). It forms a complex with MutS and MutH, increasing the MutS footprint on the DNA.

However, the processivity (the distance the enzyme can move along the DNA before dissociating) of UvrD is only ~40–50 bp. Because the distance between the nick created by MutH and the mismatch can average ~600 bp, if there is not another UvrD loaded the unwound section is then free to re-anneal to its complementary strand, forcing the process to start over. However, when assisted by MutL, the rate of UvrD loading is greatly increased. While the processivity (and ATP utilisation) of the individual UvrD molecules remains the same, the total effect on the DNA is boosted considerably; the DNA has no chance to re-anneal, as each UvrD unwinds 40-50 bp of DNA, dissociates, and then is immediately replaced by another UvrD, repeating the process. This exposes large sections of DNA to exonuclease digestion, allowing for quick excision (and later replacement) of the incorrect DNA.

Eukaryotes have MutL homologs designated Mlh1 and Pms1. They form a heterodimer that mimics MutL in E. coli. The human homologue of prokaryotic MutL has three forms designated as MutLα, MutLβ, and MutLγ. The MutLα complex is made of two subunits MLH1 and PMS2, the MutLβ heterodimer is made of MLH1 and PMS1, whereas MutLγ is made of MLH1 and MLH3. MutLα acts as the matchmaker or facilitator, coordinating events in mismatch repair. It has recently been shown to be a DNA endonuclease that introduces strand breaks in DNA upon activation by mismatch and other required proteins, MutSa and PCNA. These strand interruptions serve as entry points for an exonuclease activity that removes mismatched DNA. Roles played by MutLβ and MutLγ in mismatch repair are less-understood.

MutH: an endonuclease present in E. coli and Salmonella

MutH is a very weak endonuclease that is activated once bound to MutL (which itself is bound to MutS). It nicks unmethylated DNA and the unmethylated strand of hemimethylated DNA but does not nick fully methylated DNA. Experiments have shown that mismatch repair is random if neither strand is methylated.[citation needed] These behaviours led to the proposal that MutH determines which strand contains the mismatch. MutH has no eukaryotic homolog. Its endonuclease function is taken up by MutL homologs, which have some specialized 5'-3' exonuclease activity. The strand bias for removing mismatches from the newly synthesized daughter strand in eukaryotes may be provided by the free 3' ends of Okazaki fragments in the new strand created during replication.

PCNA β-sliding clamp

PCNA and the β-sliding clamp associate with MutSα/β and MutS, respectively. Although initial reports suggested that the PCNA-MutSα complex may enhance mismatch recognition,[5] it has been recently demonstrated[6] that there is no apparent change in affinity of MutSα for a mismatch in the presence or absence of PCNA. Furthermore, mutants of MutSα that are unable to interact with PCNA in vitro exhibit the capacity to carry out mismatch recognition and mismatch excision to near wild type levels. Such mutants are defective in the repair reaction directed by a 5' strand break, suggesting for the first time MutSα function in a post-excision step of the reaction.

Clinical significance

Inherited defects in mismatch repair

Mutations in the human homologues of the Mut proteins affect genomic stability, which can result in microsatellite instability (MSI), implicated in some human cancers. In specific, the hereditary nonpolyposis colorectal cancers (HNPCC or Lynch syndrome) are attributed to damaging germline variants in the genes encoding the MutS and MutL homologues MSH2 and MLH1 respectively, which are thus classified as tumour suppressor genes. One subtype of HNPCC, the Muir-Torre Syndrome (MTS), is associated with skin tumors. If both inherited copies (alleles) of a MMR gene bear damaging genetic variants, this results in a very rare and severe condition: the mismatch repair cancer syndrome (or constitutional mismatch repair deficiency, CMMR-D), manifesting as multiple occurrences of tumors at an early age, often colon and brain tumors.[7]

Epigenetic silencing of mismatch repair genes

Sporadic cancers with a DNA repair deficiency only rarely have a mutation in a DNA repair gene, but they instead tend to have epigenetic alterations that reduce DNA repair gene expression.[8] About 13% of colorectal cancers are deficient in DNA mismatch repair, commonly due to loss of MLH1 (9.8%), or sometimes MSH2, MSH6 or PMS2 (all ≤1.5%).[9] For most MLH1-deficient sporadic colorectal cancers, the deficiency was due to methylation of the MLH1 promoter.[9] Other cancer types have higher frequencies of MLH1 loss (see table below), which are again largely a result of methylation of the promoter of the MLH1 gene. A different epigenetic mechanism underlying MMR deficiencies might involve over-expression of a microRNA, for example miR-155 levels inversely correlate with expression of MLH1 or MSH2 in colorectal cancer.[10]

Cancers deficient in MLH1
Cancer type Frequency of deficiency in cancer Frequency of deficiency in adjacent field defect
Stomach 32%[11][12] 24%-28%
Stomach (foveolar type tumors) 74%[13] 71%
Stomach in high-incidence Kashmir Valley 73%[14] 20%
Esophageal 73%[15] 27%
Head and neck squamous cell carcinoma (HNSCC) 31%-33%[16][17] 20%-25%
Non-small cell lung cancer (NSCLC) 69%[18] 72%
Colorectal 10%[9]

MMR failures in field defects

A field defect (field cancerization) is an area of epithelium that has been preconditioned by epigenetic or genetic changes, predisposing it towards development of cancer. As pointed out by Rubin " ...there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion."[19][20] Similarly, Vogelstein et al.[21] point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.

MLH1 deficiencies were common in the field defects (histologically normal tissues) surrounding tumors; see Table above. Epigenetically silenced or mutated MLH1 would likely not confer a selective advantage upon a stem cell, however, it would cause increased mutation rates, and one or more of the mutated genes may provide the cell with a selective advantage. The deficientMLH1 gene could then be carried along as a selectively near-neutral passenger (hitch-hiker) gene when the mutated stem cell generates an expanded clone. The continued presence of a clone with an epigenetically repressed MLH1 would continue to generate further mutations, some of which could produce a tumor.

MMR components in humans

In humans, seven DNA mismatch repair (MMR) proteins (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) work coordinately in sequential steps to initiate repair of DNA mismatches.[22] In addition, there are Exo1-dependent and Exo1-independent MMR subpathways.[23]

Other gene products involved in mismatch repair (subsequent to initiation by MMR genes) in humans include DNA polymerase delta, PCNA, RPA, HMGB1, RFC and DNA ligase I, plus histone and chromatin modifying factors.[24][25]

In certain circumstances, the MMR pathway may recruit an error-prone DNA polymerase eta (POLH). This happens in B-lymphocytes during somatic hypermutation, where POLH is used to introduce genetic variation into antibody genes.[26] However, this error-prone MMR pathway may be triggered in other types of human cells upon exposure to genotoxins [27] and indeed it is broadly active in various human cancers, causing mutations that bear a signature of POLH activity.[28]

MMR and mutation frequency

Recognizing and repairing mismatches and indels is important for cells because failure to do so results in microsatellite instability (MSI) and an elevated spontaneous mutation rate (mutator phenotype). In comparison to other cancer types, MMR-deficient (MSI) cancer has a very high frequency of mutations, close to melanoma and lung cancer,[29] cancer types caused by much exposure to UV radiation and mutagenic chemicals.

In addition to a very high mutation burden, MMR deficiencies result in an unusual distribution of somatic mutations across the human genome: this suggests that MMR preferentially protects the gene-rich, early-replicating euchromatic regions.[30] In contrast, the gene-poor, late-replicating heterochromatic genome regions exhibit high mutation rates in many human tumors.[31]

The histone modification H3K36me3, an epigenetic mark of active chromatin, has the ability to recruit the MSH2-MSH6 (hMutSα) complex.[32] Consistenty, regions of the human genome with high levels of H3K36me3 accumulate less mutations due to MMR activity.[28]

Loss of multiple DNA repair pathways in tumors

Lack of MMR often occurs in coordination with loss of other DNA repair genes.[8] For example, MMR genes MLH1 and MLH3 as well as 11 other DNA repair genes (such as MGMT and many NER pathway genes) were significantly down-regulated in lower grade as well as in higher grade astrocytomas, in contrast to normal brain tissue.[33] Moreover, MLH1 and MGMT expression was closely correlated in 135 specimens of gastric cancer and loss of MLH1 and MGMT appeared to be synchronously accelerated during tumor progression.[34]

Deficient expression of multiple DNA repair genes is often found in cancers,[8] and may contribute to the thousands of mutations usually found in cancers (see Mutation frequencies in cancers).

See also

References

  1. ^ Iyer R, Pluciennik A, Burdett V, Modrich P (2006). "DNA mismatch repair: functions and mechanisms". Chem Rev. 106 (2): 302–23. PMID 16464007. doi:10.1021/cr0404794. 
  2. ^ Larrea AA, Lujan SA, Kunkel TA (2010). "DNA mismatch repair". Cell. 141 (4): 730. PMID 20478261. doi:10.1016/j.cell.2010.05.002. 
  3. ^ Heller RC, Marians KJ (2006). "Replisome assembly and the direct restart of stalled replication forks". Nat Rev Mol Cell Biol. 7 (12): 932–43. PMID 17139333. doi:10.1038/nrm2058. 
  4. ^ Pluciennik; et al. (2010). "PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair.". PNAS. 107 (37): 16066–71. PMC 2941292Freely accessible. PMID 20713735. doi:10.1073/pnas.1010662107. 
  5. ^ Flores-Rozas H, Clark D, Kolodner RD (2000). "Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex". Nature Genetics. 26 (3): 375–8. PMID 11062484. doi:10.1038/81708. 
  6. ^ Iyer RR, Pohlhaus TJ, Chen S, Hura GL, Dzantiev L, Beese LS, Modrich P (2008). "The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair". Journal of Biological Chemistry. 283 (19): 13310–9. PMC 2423938Freely accessible. PMID 18326858. doi:10.1074/jbc.M800606200. 
  7. ^ Online Mendelian Inheritance in Man (OMIM) 276300
  8. ^ a b c Bernstein C, Bernstein H (2015). "Epigenetic reduction of DNA repair in progression to gastrointestinal cancer". World J Gastrointest Oncol. 7 (5): 30–46. PMC 4434036Freely accessible. PMID 25987950. doi:10.4251/wjgo.v7.i5.30. 
  9. ^ a b c Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G (2005). "Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer". Gastroenterology. 128 (5): 1160–71. PMID 15887099. doi:10.1053/j.gastro.2005.01.056. 
  10. ^ Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM (2010). "Modulation of mismatch repair and genomic stability by miR-155". Proc. Natl. Acad. Sci. U.S.A. 107 (15): 6982–7. PMC 2872463Freely accessible. PMID 20351277. doi:10.1073/pnas.1002472107. 
  11. ^ Kupčinskaitė-Noreikienė R, Skiecevičienė J, Jonaitis L, Ugenskienė R, Kupčinskas J, Markelis R, Baltrėnas V, Sakavičius L, Semakina I, Grižas S, Juozaitytė E (2013). "CpG island methylation of the MLH1, MGMT, DAPK, and CASP8 genes in cancerous and adjacent noncancerous stomach tissues". Medicina (Kaunas). 49 (8): 361–6. PMID 24509146. 
  12. ^ Waki T, Tamura G, Tsuchiya T, Sato K, Nishizuka S, Motoyama T (2002). "Promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic gastric epithelia". Am. J. Pathol. 161 (2): 399–403. PMC 1850716Freely accessible. PMID 12163364. doi:10.1016/S0002-9440(10)64195-8. 
  13. ^ Endoh Y, Tamura G, Ajioka Y, Watanabe H, Motoyama T (2000). "Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype". Am. J. Pathol. 157 (3): 717–22. PMC 1949419Freely accessible. PMID 10980110. doi:10.1016/S0002-9440(10)64584-1. 
  14. ^ Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K (2012). "Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley". Asian Pac. J. Cancer Prev. 13 (8): 4177–81. PMID 23098428. doi:10.7314/apjcp.2012.13.8.4177. 
  15. ^ Chang Z, Zhang W, Chang Z, Song M, Qin Y, Chang F, Guo H, Wei Q (2015). "Expression characteristics of FHIT, p53, BRCA2 and MLH1 in families with a history of oesophageal cancer in a region with a high incidence of oesophageal cancer". Oncol Lett. 9 (1): 430–436. PMC 4246613Freely accessible. PMID 25436004. doi:10.3892/ol.2014.2682. 
  16. ^ Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM (2011). "Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene". Am J Otolaryngol. 32 (6): 528–36. PMID 21353335. doi:10.1016/j.amjoto.2010.11.005. 
  17. ^ Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (2009). "Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma". Otolaryngol Head Neck Surg. 141 (4): 484–90. PMID 19786217. doi:10.1016/j.otohns.2009.07.007. 
  18. ^ Safar AM, Spencer H, Su X, Coffey M, Cooney CA, Ratnasinghe LD, Hutchins LF, Fan CY (2005). "Methylation profiling of archived non-small cell lung cancer: a promising prognostic system". Clin. Cancer Res. 11 (12): 4400–5. PMID 15958624. doi:10.1158/1078-0432.CCR-04-2378. 
  19. ^ Rubin H (March 2011). "Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture". BioEssays. 33 (3): 224–31. PMID 21254148. doi:10.1002/bies.201000067. 
  20. ^ Tsao JL, Yatabe Y, Salovaara R, Järvinen HJ, Mecklin JP, Aaltonen LA, Tavaré S, Shibata D (February 2000). "Genetic reconstruction of individual colorectal tumor histories". Proc. Natl. Acad. Sci. U.S.A. 97 (3): 1236–41. PMC 15581Freely accessible. PMID 10655514. doi:10.1073/pnas.97.3.1236. 
  21. ^ Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (March 2013). "Cancer genome landscapes". Science. 339 (6127): 1546–58. PMC 3749880Freely accessible. PMID 23539594. doi:10.1126/science.1235122. 
  22. ^ Pal T, Permuth-Wey J, Sellers TA (2008). "A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer". Cancer. 113 (4): 733–42. PMC 2644411Freely accessible. PMID 18543306. doi:10.1002/cncr.23601. 
  23. ^ Goellner EM, Putnam CD, Kolodner RD (2015). "Exonuclease 1-dependent and independent mismatch repair". DNA Repair (Amst.). 32: 24–32. PMC 4522362Freely accessible. PMID 25956862. doi:10.1016/j.dnarep.2015.04.010. 
  24. ^ Li GM (2008). "Mechanisms and functions of DNA mismatch repair". Cell Res. 18 (1): 85–98. PMID 18157157. doi:10.1038/cr.2007.115. 
  25. ^ Li GM (2014). "New insights and challenges in mismatch repair: getting over the chromatin hurdle". DNA Repair (Amst.). 19: 48–54. PMC 4127414Freely accessible. PMID 24767944. doi:10.1016/j.dnarep.2014.03.027. 
  26. ^ Chahwan, Richard; Edelmann, Winfried; Scharff, Matthew D; Roa, Sergio (August 2012). "AIDing antibody diversity by error-prone mismatch repair". Seminars in immunology. 24 (4): 293–300. ISSN 1044-5323. PMC 3422444Freely accessible. PMID 22703640. doi:10.1016/j.smim.2012.05.005. 
  27. ^ Hsieh, Peggy (2012-09-14). "DNA Mismatch Repair: Dr. Jekyll and Mr. Hyde?". Molecular Cell. 47 (5): 665–666. ISSN 1097-2765. PMC 3457060Freely accessible. PMID 22980456. doi:10.1016/j.molcel.2012.08.020. 
  28. ^ a b Supek, Fran; Lehner, Ben (2017-07-27). "Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes". Cell. 170 (3): 534–547.e23. ISSN 1097-4172. PMID 28753428. doi:10.1016/j.cell.2017.07.003. 
  29. ^ Tuna M, Amos CI (2013). "Genomic sequencing in cancer". Cancer Lett. 340 (2): 161–70. PMC 3622788Freely accessible. PMID 23178448. doi:10.1016/j.canlet.2012.11.004. 
  30. ^ Supek, Fran; Lehner, Ben (2015-05-07). "Differential DNA mismatch repair underlies mutation rate variation across the human genome". Nature. 521 (7550): 81–84. ISSN 1476-4687. PMC 4425546Freely accessible. PMID 25707793. doi:10.1038/nature14173. 
  31. ^ Schuster-Böckler, Benjamin; Lehner, Ben (2012-08-23). "Chromatin organization is a major influence on regional mutation rates in human cancer cells". Nature. 488 (7412): 504–507. ISSN 1476-4687. PMID 22820252. doi:10.1038/nature11273. 
  32. ^ Li, Feng; Mao, Guogen; Tong, Dan; Huang, Jian; Gu, Liya; Yang, Wei; Li, Guo-Min (2013-04-25). "The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through its Interaction with MutSα". Cell. 153 (3): 590–600. ISSN 0092-8674. PMC 3641580Freely accessible. PMID 23622243. doi:10.1016/j.cell.2013.03.025. 
  33. ^ Jiang Z, Hu J, Li X, Jiang Y, Zhou W, Lu D (2006). "Expression analyses of 27 DNA repair genes in astrocytoma by TaqMan low-density array". Neurosci. Lett. 409 (2): 112–7. PMID 17034947. doi:10.1016/j.neulet.2006.09.038. 
  34. ^ Kitajima Y, Miyazaki K, Matsukura S, Tanaka M, Sekiguchi M (2003). "Loss of expression of DNA repair enzymes MGMT, hMLH1, and hMSH2 during tumor progression in gastric cancer". Gastric Cancer. 6 (2): 86–95. PMID 12861399. doi:10.1007/s10120-003-0213-z. 

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DNA mismatch repair protein, C-terminal domain Provide feedback

This family represents the C-terminal domain of the mutL/hexB/PMS1 family. This domain has a ribosomal S5 domain 2-like fold.

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This tab holds annotation information from the InterPro database.

InterPro entry IPR013507

This entry represents the C-terminal domain of DNA mismatch repair proteins, such as MutL. This domain functions in promoting dimerisation [PUBMED:16024043]. The dimeric MutL protein has a key function in communicating mismatch recognition by MutS to downstream repair processes. Mismatch repair contributes to the overall fidelity of DNA replication by targeting mispaired bases that arise through replication errors during homologous recombination and as a result of DNA damage. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex [PUBMED:14527292].

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan S5 (CL0329), which has the following description:

This superfamily contains a wide range of families that possess a structure similar to the second domain of ribosomal S5 protein.

The clan contains the following 17 members:

ChlI DNA_gyraseB DNA_mis_repair EFG_IV Fae GalKase_gal_bdg GHMP_kinases_N IGPD Lon_C LpxC Ribonuclease_P Ribosomal_S5_C Ribosomal_S9 RNase_PH Topo-VIb_trans UPF0029 Xol-1_N

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: SCOP
Previous IDs: none
Type: Family
Author: Finn RD, Bateman A, Griffiths-Jones SR
Number in seed: 126
Number in full: 5404
Average length of the domain: 118.50 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 16.84 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.6 20.6
Noise cut-off 20.5 20.5
Model length: 119
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 2 interactions for this family. More...

HATPase_c HATPase_c_3

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DNA_mis_repair domain has been found. There are 31 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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