Mismatch repair endonuclease PMS2

Details

Name
Mismatch repair endonuclease PMS2
Synonyms
  • 3.1.-.-
  • DNA mismatch repair protein PMS2
  • PMS1 protein homolog 2
  • PMSL2
Gene Name
PMS2
Organism
Humans
Amino acid sequence
>lcl|BSEQ0037213|Mismatch repair endonuclease PMS2
MERAESSSTEPAKAIKPIDRKSVHQICSGQVVLSLSTAVKELVENSLDAGATNIDLKLKD
YGVDLIEVSDNGCGVEEENFEGLTLKHHTSKIQEFADLTQVETFGFRGEALSSLCALSDV
TISTCHASAKVGTRLMFDHNGKIIQKTPYPRPRGTTVSVQQLFSTLPVRHKEFQRNIKKE
YAKMVQVLHAYCIISAGIRVSCTNQLGQGKRQPVVCTGGSPSIKENIGSVFGQKQLQSLI
PFVQLPPSDSVCEEYGLSCSDALHNLFYISGFISQCTHGVGRSSTDRQFFFINRRPCDPA
KVCRLVNEVYHMYNRHQYPFVVLNISVDSECVDINVTPDKRQILLQEEKLLLAVLKTSLI
GMFDSDVNKLNVSQQPLLDVEGNLIKMHAADLEKPMVEKQDQSPSLRTGEEKKDVSISRL
REAFSLRHTTENKPHSPKTPEPRRSPLGQKRGMLSSSTSGAISDKGVLRPQKEAVSSSHG
PSDPTDRAEVEKDSGHGSTSVDSEGFSIPDTGSHCSSEYAASSPGDRGSQEHVDSQEKAP
KTDDSFSDVDCHSNQEDTGCKFRVLPQPTNLATPNTKRFKKEEILSSSDICQKLVNTQDM
SASQVDVAVKINKKVVPLDFSMSSLAKRIKQLHHEAQQSEGEQNYRKFRAKICPGENQAA
EDELRKEISKTMFAEMEIIGQFNLGFIITKLNEDIFIVDQHATDEKYNFEMLQQHTVLQG
QRLIAPQTLNLTAVNEAVLIENLEIFRKNGFDFVIDENAPVTERAKLISLPTSKNWTFGP
QDVDELIFMLSDSPGVMCRPSRVKQMFASRACRKSVMIGTALNTSEMKKLITHMGEMDHP
WNCPHGRPTMRHIANLGVISQN
Number of residues
862
Molecular Weight
95795.875
Theoretical pI
6.72
GO Classification
Functions
ATP binding / ATPase activity / DNA binding / endonuclease activity / single base insertion or deletion binding
Processes
DNA repair / mismatch repair / nucleic acid phosphodiester bond hydrolysis / somatic hypermutation of immunoglobulin genes / somatic recombination of immunoglobulin gene segments
Components
cytoplasm / microtubule cytoskeleton / MutLalpha complex / nucleoplasm / nucleus
General Function
Single base insertion or deletion binding
Specific Function
Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MLH1 to form MutL alpha. DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0016910|Mismatch repair endonuclease PMS2 (PMS2)
ATGGAGCGAGCTGAGAGCTCGAGTACAGAACCTGCTAAGGCCATCAAACCTATTGATCGG
AAGTCAGTCCATCAGATTTGCTCTGGGCAGGTGGTACTGAGTCTAAGCACTGCGGTAAAG
GAGTTAGTAGAAAACAGTCTGGATGCTGGTGCCACTAATATTGATCTAAAGCTTAAGGAC
TATGGAGTGGATCTTATTGAAGTTTCAGACAATGGATGTGGGGTAGAAGAAGAAAACTTC
GAAGGCTTAACTCTGAAACATCACACATCTAAGATTCAAGAGTTTGCCGACCTAACTCAG
GTTGAAACTTTTGGCTTTCGGGGGGAAGCTCTGAGCTCACTTTGTGCACTGAGCGATGTC
ACCATTTCTACCTGCCACGCATCGGCGAAGGTTGGAACTCGACTGATGTTTGATCACAAT
GGGAAAATTATCCAGAAAACCCCCTACCCCCGCCCCAGAGGGACCACAGTCAGCGTGCAG
CAGTTATTTTCCACACTACCTGTGCGCCATAAGGAATTTCAAAGGAATATTAAGAAGGAG
TATGCCAAAATGGTCCAGGTCTTACATGCATACTGTATCATTTCAGCAGGCATCCGTGTA
AGTTGCACCAATCAGCTTGGACAAGGAAAACGACAGCCTGTGGTATGCACAGGTGGAAGC
CCCAGCATAAAGGAAAATATCGGCTCTGTGTTTGGGCAGAAGCAGTTGCAAAGCCTCATT
CCTTTTGTTCAGCTGCCCCCTAGTGACTCCGTGTGTGAAGAGTACGGTTTGAGCTGTTCC
GATGCTCTGCATAATCTTTTTTACATCTCAGGTTTCATTTCACAATGCACGCATGGAGTT
GGAAGGAGTTCAACAGACAGACAGTTTTTCTTTATCAACCGGCGGCCTTGTGACCCAGCA
AAGGTCTGCAGACTCGTGAATGAGGTCTACCACATGTATAATCGACACCAGTATCCATTT
GTTGTTCTTAACATTTCTGTTGATTCAGAATGCGTTGATATCAATGTTACTCCAGATAAA
AGGCAAATTTTGCTACAAGAGGAAAAGCTTTTGTTGGCAGTTTTAAAGACCTCTTTGATA
GGAATGTTTGATAGTGATGTCAACAAGCTAAATGTCAGTCAGCAGCCACTGCTGGATGTT
GAAGGTAACTTAATAAAAATGCATGCAGCGGATTTGGAAAAGCCCATGGTAGAAAAGCAG
GATCAATCCCCTTCATTAAGGACTGGAGAAGAAAAAAAAGACGTGTCCATTTCCAGACTG
CGAGAGGCCTTTTCTCTTCGTCACACAACAGAGAACAAGCCTCACAGCCCAAAGACTCCA
GAACCAAGAAGGAGCCCTCTAGGACAGAAAAGGGGTATGCTGTCTTCTAGCACTTCAGGT
GCCATCTCTGACAAAGGCGTCCTGAGACCTCAGAAAGAGGCAGTGAGTTCCAGTCACGGA
CCCAGTGACCCTACGGACAGAGCGGAGGTGGAGAAGGACTCGGGGCACGGCAGCACTTCC
GTGGATTCTGAGGGGTTCAGCATCCCAGACACGGGCAGTCACTGCAGCAGCGAGTATGCG
GCCAGCTCCCCAGGGGACAGGGGCTCGCAGGAACATGTGGACTCTCAGGAGAAAGCGCCT
GAAACTGACGACTCTTTTTCAGATGTGGACTGCCATTCAAACCAGGAAGATACCGGATGT
AAATTTCGAGTTTTGCCTCAGCCAACTAATCTCGCAACCCCAAACACAAAGCGTTTTAAA
AAAGAAGAAATTCTTTCCAGTTCTGACATTTGTCAAAAGTTAGTAAATACTCAGGACATG
TCAGCCTCTCAGGTTGATGTAGCTGTGAAAATTAATAAGAAAGTTGTGCCCCTGGACTTT
TCTATGAGTTCTTTAGCTAAACGAATAAAGCAGTTACATCATGAAGCACAGCAAAGTGAA
GGGGAACAGAATTACAGGAAGTTTAGGGCAAAGATTTGTCCTGGAGAAAATCAAGCAGCC
GAAGATGAACTAAGAAAAGAGATAAGTAAAACGATGTTTGCAGAAATGGAAATCATTGGT
CAGTTTAACCTGGGATTTATAATAACCAAACTGAATGAGGATATCTTCATAGTGGACCAG
CATGCCACGGACGAGAAGTATAACTTCGAGATGCTGCAGCAGCACACCGTGCTCCAGGGG
CAGAGGCTCATAGCACCTCAGACTCTCAACTTAACTGCTGTTAATGAAGCTGTTCTGATA
GAAAATCTGGAAATATTTAGAAAGAATGGCTTTGATTTTGTTATCGATGAAAATGCTCCA
GTCACTGAAAGGGCTAAACTGATTTCCTTGCCAACTAGTAAAAACTGGACCTTCGGACCC
CAGGACGTCGATGAACTGATCTTCATGCTGAGCGACAGCCCTGGGGTCATGTGCCGGCCT
TCCCGAGTCAAGCAGATGTTTGCCTCCAGAGCCTGCCGGAAGTCGGTGATGATTGGGACT
GCTCTTAACACAAGCGAGATGAAGAAACTGATCACCCACATGGGGGAGATGGACCACCCC
TGGAACTGTCCCCATGGAAGGCCAACCATGAGACACATCGCCAACCTGGGTGTCATTTCT
CAGAACTGA
Chromosome Location
7
Locus
7p22.2
External Identifiers
ResourceLink
UniProtKB IDP54278
UniProtKB Entry NamePMS2_HUMAN
GenBank Gene IDU13696
GenAtlas IDPMS2
HGNC IDHGNC:9122
General References
  1. Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994 Sep 1;371(6492):75-80. [PubMed:8072530]
  2. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039]
  3. Hillier LW, Fulton RS, Fulton LA, Graves TA, Pepin KH, Wagner-McPherson C, Layman D, Maas J, Jaeger S, Walker R, Wylie K, Sekhon M, Becker MC, O'Laughlin MD, Schaller ME, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Cordes M, Du H, Sun H, Edwards J, Bradshaw-Cordum H, Ali J, Andrews S, Isak A, Vanbrunt A, Nguyen C, Du F, Lamar B, Courtney L, Kalicki J, Ozersky P, Bielicki L, Scott K, Holmes A, Harkins R, Harris A, Strong CM, Hou S, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Leonard S, Rohlfing T, Rock SM, Tin-Wollam AM, Abbott A, Minx P, Maupin R, Strowmatt C, Latreille P, Miller N, Johnson D, Murray J, Woessner JP, Wendl MC, Yang SP, Schultz BR, Wallis JW, Spieth J, Bieri TA, Nelson JO, Berkowicz N, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Bedell JA, Mardis ER, Clifton SW, Chissoe SL, Marra MA, Raymond C, Haugen E, Gillett W, Zhou Y, James R, Phelps K, Iadanoto S, Bubb K, Simms E, Levy R, Clendenning J, Kaul R, Kent WJ, Furey TS, Baertsch RA, Brent MR, Keibler E, Flicek P, Bork P, Suyama M, Bailey JA, Portnoy ME, Torrents D, Chinwalla AT, Gish WR, Eddy SR, McPherson JD, Olson MV, Eichler EE, Green ED, Waterston RH, Wilson RK: The DNA sequence of human chromosome 7. Nature. 2003 Jul 10;424(6945):157-64. [PubMed:12853948]
  4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  5. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J: BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000 Apr 15;14(8):927-39. [PubMed:10783165]
  6. Worthley DL, Walsh MD, Barker M, Ruszkiewicz A, Bennett G, Phillips K, Suthers G: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology. 2005 May;128(5):1431-6. [PubMed:15887124]
  7. Kadyrov FA, Dzantiev L, Constantin N, Modrich P: Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006 Jul 28;126(2):297-308. [PubMed:16873062]
  8. Clendenning M, Senter L, Hampel H, Robinson KL, Sun S, Buchanan D, Walsh MD, Nilbert M, Green J, Potter J, Lindblom A, de la Chapelle A: A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. J Med Genet. 2008 Jun;45(6):340-5. doi: 10.1136/jmg.2007.056150. Epub 2008 Jan 4. [PubMed:18178629]
  9. Sacho EJ, Kadyrov FA, Modrich P, Kunkel TA, Erie DA: Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha. Mol Cell. 2008 Jan 18;29(1):112-21. doi: 10.1016/j.molcel.2007.10.030. [PubMed:18206974]
  10. Constantin N, Dzantiev L, Kadyrov FA, Modrich P: Human mismatch repair: reconstitution of a nick-directed bidirectional reaction. J Biol Chem. 2005 Dec 2;280(48):39752-61. Epub 2005 Sep 27. [PubMed:16188885]
  11. Jiricny J: MutLalpha: at the cutting edge of mismatch repair. Cell. 2006 Jul 28;126(2):239-41. [PubMed:16873053]
  12. Li GM: Mechanisms and functions of DNA mismatch repair. Cell Res. 2008 Jan;18(1):85-98. [PubMed:18157157]
  13. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge SJ: A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010 Jul 9;39(1):36-47. doi: 10.1016/j.molcel.2010.06.023. [PubMed:20603073]
  14. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [PubMed:20068231]
  15. Guarne A, Junop MS, Yang W: Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J. 2001 Oct 1;20(19):5521-31. [PubMed:11574484]
  16. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al.: The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839-47. [PubMed:7661930]
  17. Miyaki M, Nishio J, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Nagato M, Chong JM, Koike M, Terada T, Kawahara Y, Fukutome A, Tomiyama J, Chuganji Y, Momoi M, Utsunomiya J: Drastic genetic instability of tumors and normal tissues in Turcot syndrome. Oncogene. 1997 Dec 4;15(23):2877-81. [PubMed:9419979]
  18. Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A: Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet. 1999 Jul-Aug;105(1-2):79-85. [PubMed:10480359]
  19. Yuan ZQ, Gottlieb B, Beitel LK, Wong N, Gordon PH, Wang Q, Puisieux A, Foulkes WD, Trifiro M: Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms. Hum Mutat. 2002 Feb;19(2):108-13. [PubMed:11793469]
  20. De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT: Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet. 2004 May;74(5):954-64. Epub 2004 Apr 7. [PubMed:15077197]
  21. Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q: Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007 Nov;28(11):1084-90. [PubMed:17557300]
  22. Borras E, Pineda M, Cadinanos J, Del Valle J, Brieger A, Hinrichsen I, Cabanillas R, Navarro M, Brunet J, Sanjuan X, Musulen E, van der Klift H, Lazaro C, Plotz G, Blanco I, Capella G: Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet. 2013 Aug;50(8):552-63. doi: 10.1136/jmedgenet-2012-101511. Epub 2013 May 24. [PubMed:23709753]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02930Adenosine 5'-[gamma-thio]triphosphateexperimentalunknownDetails