Reviewed, UniProtKB/Swiss-Prot P54278 (PMS2_HUMAN)

Names and origin

Protein names

Recommended name:
    Mismatch repair endonuclease PMS2
    EC=3.1.-.-
Alternative name(s):
    PMS1 protein homolog 2
    DNA mismatch repair protein PMS2

Gene names

Name:	PMS2
Synonyms:	PMSL2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	862 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

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. MulL 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.
Subunit structure	Heterodimer of PMS2 and MLH1 (MutL alpha). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains.
Subcellular location	Nucleus.
Involvement in disease	Defects in PMS2 are the cause of hereditary non-polyposis colorectal cancer type 4 (HNPCC4) [MIM:600259]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. Defects in PMS2 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:276300]; also known as Turcot syndrome and brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.
Sequence similarities	Belongs to the DNA mismatch repair mutL/hexB family.

Ontologies

Keywords
Biological process	Cell cycle DNA damage DNA repair
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Hereditary nonpolyposis colorectal cancer
Molecular function	Anti-oncogene Endonuclease Hydrolase Nuclease
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	mismatch repair Inferred from direct assay. Source: HGNC negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred by curator. Source: HGNC
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro endonuclease activity Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.17 Inferred from physical interaction. Source: IntAct single base insertion or deletion binding Inferred from direct assay. Source: HGNC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MLH1	P40692	1	EBI-1162561,EBI-744248

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P54278-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Notes: No experimental confirmation available.

Isoform 2 (identifier: P54278-2)

The sequence of this isoform differs from the canonical sequence as follows:
     269-669: Missing.

Notes: No experimental confirmation available.

Isoform 3 (identifier: P54278-3)

The sequence of this isoform differs from the canonical sequence as follows:
     560-572: CKFRVLPQPTNLA → LKTGPSDPRTSMN
     573-862: Missing.

Notes: No experimental confirmation available.

Isoform 4 (identifier: P54278-4)

The sequence of this isoform differs from the canonical sequence as follows:
     180-183: EYAK → QASV
     184-862: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 862

862

Mismatch repair endonuclease PMS2

PRO_0000178005

Amino acid modifications

Modified residue

181

1

Phosphotyrosine By similarity

Modified residue

403

1

Phosphoserine

Modified residue

573

1

Phosphothreonine

Natural variations

Alternative sequence

180 – 183

4

EYAK → QASV in isoform 4.

VSP_029384

Alternative sequence

184 – 862

679

Missing in isoform 4.

VSP_029385

Alternative sequence

269 – 669

401

Missing in isoform 2.

VSP_029386

Alternative sequence

560 – 572

13

CKFRV…PTNLA → LKTGPSDPRTSMN in isoform 3.

VSP_029387

Alternative sequence

573 – 862

290

Missing in isoform 3.

VSP_029388

Natural variant

20

1

R → Q: dbSNP rs10254120.

VAR_004469

Natural variant

277

1

T → K: dbSNP rs1805322.

VAR_016133

Natural variant

470

1

P → S: dbSNP rs1805321.

VAR_016134

Natural variant

479

1

H → Q

VAR_012969

Natural variant

485

1

T → K: dbSNP rs1805323.

VAR_012970

Natural variant

511

1

T → A: dbSNP rs2228007.

VAR_012971

Natural variant

541

1

E → K: dbSNP rs2228006.

VAR_024541

Natural variant

597

1

T → S May be associated with increased susceptibility to colorectal cancer; significantly reduced interaction with MLH1. dbSNP rs1805318.

VAR_012972

Natural variant

622

1

M → I May be associated with increased susceptibility to colorectal cancer; significantly reduced interaction with MLH1. dbSNP rs1805324.

VAR_012973

Natural variant

705

1

E → K in MMRCS; could be a rare polymorphism.

VAR_012974

Natural variant

775

1

N → S: dbSNP rs1059060.

VAR_016135

Secondary structure

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862

Helix Strand Turn

Details...

Beta strand

30 – 32

3

Helix

35 – 48

14

Beta strand

52 – 59

8

Helix

60 – 62

3

Beta strand

64 – 70

7

Helix

77 – 79

3

Helix

81 – 84

4

Beta strand

101 – 109

9

Helix

110 – 117

8

Beta strand

118 – 125

8

Beta strand

133 – 137

5

Beta strand

143 – 148

6

Beta strand

153 – 161

9

Turn

162 – 165

4

Helix

167 – 175

9

Helix

177 – 194

18

Beta strand

199 – 205

7

Beta strand

211 – 216

6

Helix

223 – 231

9

Helix

233 – 237

5

Beta strand

239 – 241

3

Helix

249 – 255

7

Turn

259 – 263

5

Beta strand

268 – 274

7

Turn

278 – 280

3

Beta strand

281 – 285

5

Beta strand

288 – 292

5

Beta strand

295 – 297

3

Helix

300 – 311

12

Beta strand

321 – 326

6

Helix

329 – 331

3

Beta strand

332 – 334

3

Beta strand

343 – 345

3

Helix

348 – 363

16

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: B60A605222CBBCAC	FASTA	862	95,798
	10 20 30 40 50 60 MERAESSSTE PAKAIKPIDR KSVHQICSGQ VVLSLSTAVK ELVENSLDAG ATNIDLKLKD 70 80 90 100 110 120 YGVDLIEVSD NGCGVEEENF EGLTLKHHTS KIQEFADLTQ VETFGFRGEA LSSLCALSDV 130 140 150 160 170 180 TISTCHASAK VGTRLMFDHN GKIIQKTPYP RPRGTTVSVQ QLFSTLPVRH KEFQRNIKKE 190 200 210 220 230 240 YAKMVQVLHA YCIISAGIRV SCTNQLGQGK RQPVVCTGGS PSIKENIGSV FGQKQLQSLI 250 260 270 280 290 300 PFVQLPPSDS VCEEYGLSCS DALHNLFYIS GFISQCTHGV GRSSTDRQFF FINRRPCDPA 310 320 330 340 350 360 KVCRLVNEVY HMYNRHQYPF VVLNISVDSE CVDINVTPDK RQILLQEEKL LLAVLKTSLI 370 380 390 400 410 420 GMFDSDVNKL NVSQQPLLDV EGNLIKMHAA DLEKPMVEKQ DQSPSLRTGE EKKDVSISRL 430 440 450 460 470 480 REAFSLRHTT ENKPHSPKTP EPRRSPLGQK RGMLSSSTSG AISDKGVLRP QKEAVSSSHG 490 500 510 520 530 540 PSDPTDRAEV EKDSGHGSTS VDSEGFSIPD TGSHCSSEYA ASSPGDRGSQ EHVDSQEKAP 550 560 570 580 590 600 ETDDSFSDVD CHSNQEDTGC KFRVLPQPTN LATPNTKRFK KEEILSSSDI CQKLVNTQDM 610 620 630 640 650 660 SASQVDVAVK INKKVVPLDF SMSSLAKRIK QLHHEAQQSE GEQNYRKFRA KICPGENQAA 670 680 690 700 710 720 EDELRKEISK TMFAEMEIIG QFNLGFIITK LNEDIFIVDQ HATDEKYNFE MLQQHTVLQG 730 740 750 760 770 780 QRLIAPQTLN LTAVNEAVLI ENLEIFRKNG FDFVIDENAP VTERAKLISL PTSKNWTFGP 790 800 810 820 830 840 QDVDELIFML SDSPGVMCRP SRVKQMFASR ACRKSVMIGT ALNTSEMKKL ITHMGEMDHP 850 860 WNCPHGRPTM RHIANLGVIS QN
	Isoform 2 [UniParc]. Checksum: 26A7DCBA84C6FEA5		461	51,251
	10 20 30 40 50 60 MERAESSSTE PAKAIKPIDR KSVHQICSGQ VVLSLSTAVK ELVENSLDAG ATNIDLKLKD 70 80 90 100 110 120 YGVDLIEVSD NGCGVEEENF EGLTLKHHTS KIQEFADLTQ VETFGFRGEA LSSLCALSDV 130 140 150 160 170 180 TISTCHASAK VGTRLMFDHN GKIIQKTPYP RPRGTTVSVQ QLFSTLPVRH KEFQRNIKKE 190 200 210 220 230 240 YAKMVQVLHA YCIISAGIRV SCTNQLGQGK RQPVVCTGGS PSIKENIGSV FGQKQLQSLI 250 260 270 280 290 300 PFVQLPPSDS VCEEYGLSCS DALHNLFYKT MFAEMEIIGQ FNLGFIITKL NEDIFIVDQH 310 320 330 340 350 360 ATDEKYNFEM LQQHTVLQGQ RLIAPQTLNL TAVNEAVLIE NLEIFRKNGF DFVIDENAPV 370 380 390 400 410 420 TERAKLISLP TSKNWTFGPQ DVDELIFMLS DSPGVMCRPS RVKQMFASRA CRKSVMIGTA 430 440 450 460 LNTSEMKKLI THMGEMDHPW NCPHGRPTMR HIANLGVISQ N
	Isoform 3 [UniParc]. Checksum: D205376091F469AA		572	62,752
	10 20 30 40 50 60 MERAESSSTE PAKAIKPIDR KSVHQICSGQ VVLSLSTAVK ELVENSLDAG ATNIDLKLKD 70 80 90 100 110 120 YGVDLIEVSD NGCGVEEENF EGLTLKHHTS KIQEFADLTQ VETFGFRGEA LSSLCALSDV 130 140 150 160 170 180 TISTCHASAK VGTRLMFDHN GKIIQKTPYP RPRGTTVSVQ QLFSTLPVRH KEFQRNIKKE 190 200 210 220 230 240 YAKMVQVLHA YCIISAGIRV SCTNQLGQGK RQPVVCTGGS PSIKENIGSV FGQKQLQSLI 250 260 270 280 290 300 PFVQLPPSDS VCEEYGLSCS DALHNLFYIS GFISQCTHGV GRSSTDRQFF FINRRPCDPA 310 320 330 340 350 360 KVCRLVNEVY HMYNRHQYPF VVLNISVDSE CVDINVTPDK RQILLQEEKL LLAVLKTSLI 370 380 390 400 410 420 GMFDSDVNKL NVSQQPLLDV EGNLIKMHAA DLEKPMVEKQ DQSPSLRTGE EKKDVSISRL 430 440 450 460 470 480 REAFSLRHTT ENKPHSPKTP EPRRSPLGQK RGMLSSSTSG AISDKGVLRP QKEAVSSSHG 490 500 510 520 530 540 PSDPTDRAEV EKDSGHGSTS VDSEGFSIPD TGSHCSSEYA ASSPGDRGSQ EHVDSQEKAP 550 560 570 ETDDSFSDVD CHSNQEDTGL KTGPSDPRTS MN
	Isoform 4 [UniParc]. Checksum: ECC6B3983021FF07		183	20,073
	10 20 30 40 50 60 MERAESSSTE PAKAIKPIDR KSVHQICSGQ VVLSLSTAVK ELVENSLDAG ATNIDLKLKD 70 80 90 100 110 120 YGVDLIEVSD NGCGVEEENF EGLTLKHHTS KIQEFADLTQ VETFGFRGEA LSSLCALSDV 130 140 150 160 170 180 TISTCHASAK VGTRLMFDHN GKIIQKTPYP RPRGTTVSVQ QLFSTLPVRH KEFQRNIKKQ ASV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mutations of two PMS homologues in hereditary nonpolyposis colon cancer." Nicolaides N.C., Papadopoulos N., Liu B., Wei Y.-F., Carter K.C., Ruben S.M., Rosen C.A., Haseltine W.H., Fleischmann R.D., Fraser C.M., Adams M.D., Venter J.C., Dunlop M.G., Hamilton S.R., Petersen G.M., de la Chapelle A., Vogelstein B., Kinzler K.W. Nature 371:75-80(1994) [PubMed: 8072530] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-20. Tissue: Endometrial tumor.
[2]	"PMS2 mRNA, nirs splice variants." Tabata Y., Sameshima E., Hayashi A., Iida K., Mitsuyama M., Kanai S., Furuya T., Saito T. Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4).
[3]	Bronner C.E., Baker S.M., Morrison P.T., Warren G., Smith L.G., Lescoe M.K., Kane M.F., Earibino C., Lipford J., Lindblom A., Tannergaard P., Bollag R.J., Godwin A.R., Ward D.C., Nordenskjoeld M., Fishel R., Kolodner R.D., Liskay R.M. Submitted (OCT-1994) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-470.
[4]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S.,