MISMATCH REPAIR PATHWAY (PW:0000662)
Description DNA
mismatch repair (MMR) represents a highly conserved pathway that assures the correct
base matching of the duplex. Despite the high replication fidelity of
polymerases, mismatched bases may be introduced into the daughter strand during
DNA replication; small deletion/insertion loops may be introduced during replication
of repetitive DNA tracts. If uncorrected, mismatches will give rise to potentially
deleterious mutations. MMR pathway has been well studied and characterized in E. coli. In eukaryotes, the best characterized
system is
S. cerevisiae ; human
components have been identified and assayed in cell extracts and reconstituted
systems.
E. coli MMR is initiated by
recognition of mismatched bases by MutS; MutL relays MutS activity to downstream
events. Msh proteins are the mammalian counterparts of MutS; Mlh and Pms
proteins are the counterparts of MutL. Base excision is mediated by Exo1; protection
of ssDNA and prevention of hairpin formation is provided by Rpa - a trimeric
single-stranded DNA-binding protein complex. Repair of the single-stranded gap
involves re-synthesis and ligation carried out by DNA polymerase delta and DNA
ligase 1. Several polymerases maintain the integrity of the genome by carrying
out DNA replication, recombination and repair. Delta and epsilon polymerases are
involved in DNA replication and in DNA base and strand repair pathways; only delta
appears to be specifically involved in MMR. Base excision and nucleotide
excision are base repair pathways that fix DNA damaged by exogenous or
endogenous agents. Polymerase delta requires a moving platform; this is
provided by the processivity factor Pcna (known as the clamp) and a pentameric
protein complex Rfc (Replication factor C) that loads it (known as the
clamp-loader). Rfc binds the ring shaped Pcna in the presence of ATP; ATP-bound
Rfc binds DNA and this event prompts ATP hydrolysis and ejection of the Rfc
complex. The now closed Pcna clamp on DNA is in the proper orientation for use
by the polymerase. Delta polymerase and Rcf appear to bind/compete for the same
site on the Pcna clamp. Interactions between components of MMR and between some
of these components and other proteins have been established; the significance
of many remains elusive. And so are many of the molecular details of the
pathway such as strand specificity and recognition or Rpa clearance amongst
them. Alterations in MMR pathway have been implicated in colorectal and other
forms of cancer.
To see the ontology report for annotations, GViewer and
download, click here [click to see the ontology
report for associated GO term - GO:0006298 and KEGG map - map03430 ]...(less)
Pathway Diagram:
Genes in Pathway:
G
Exo1 exonuclease 1
13
93,936,989
93,962,749
RGD:2306716 RGD:6907045
G
Hmgb1 high mobility group box 1
12
7,082,529
7,090,246
RGD:2306716
G
Lig1 DNA ligase 1
1
75,356,212
75,394,757
RGD:2306716 RGD:6907045
G
Mlh1 mutL homolog 1
8
119,486,655
119,523,716
RGD:2306716 RGD:6907045
G
Mlh3 mutL homolog 3
6
109,059,386
109,095,876
RGD:2306716 RGD:6907045
G
Msh2 mutS homolog 2
6
11,215,951
11,274,916
RGD:2306716 RGD:6907045
G
Msh3 mutS homolog 3
2
21,790,048
21,931,791
RGD:2306716 RGD:6907045
G
Msh6 mutS homolog 6
6
11,644,565
11,662,389
RGD:2306716
G
Pcna proliferating cell nuclear antigen
3
124,880,698
124,884,570
RGD:2306716 RGD:6907045
G
Pms1 PMS1 homolog 1, mismatch repair system component
9
53,120,656
53,206,520
RGD:2306716
G
Pms2 PMS1 homolog 2, mismatch repair system component
12
12,714,394
12,738,654
RGD:2306716 RGD:6907045
G
Pold1 DNA polymerase delta 1, catalytic subunit
1
100,538,066
100,554,105
RGD:2306716 RGD:6907045
G
Pold2 DNA polymerase delta 2, accessory subunit
14
86,111,416
86,117,578
RGD:2306716 RGD:6907045
G
Pold3 DNA polymerase delta 3, accessory subunit
1
165,085,142
165,122,385
RGD:2306716 RGD:6907045
G
Pold4 DNA polymerase delta 4, accessory subunit
1
219,480,841
219,483,244
RGD:2306716 RGD:6907045
G
Rfc1 replication factor C subunit 1
14
44,627,528
44,702,205
RGD:2306716 RGD:6907045
G
Rfc2 replication factor C subunit 2
12
25,130,375
25,143,480
RGD:2306716 RGD:6907045
G
Rfc3 replication factor C subunit 3
12
1,460,581
1,471,344
RGD:2306716 RGD:6907045
G
Rfc4 replication factor C subunit 4
11
81,358,592
81,373,044
RGD:2306716 RGD:6907045
G
Rfc5 replication factor C subunit 5
12
44,931,494
44,941,051
RGD:2306716 RGD:6907045
G
Rpa1 replication protein A1
10
62,140,419
62,191,518
RGD:2306716 RGD:6907045
G
Rpa2 replication protein A2
5
150,957,041
150,967,597
RGD:2306716 RGD:6907045
G
Rpa3 replication protein A3
4
34,279,320
34,282,351
RGD:2306716 RGD:6907045
G
Ssbp1 single stranded DNA binding protein 1
4
68,634,844
68,645,112
RGD:6907045
G
Mlh1 mutL homolog 1
8
119,486,655
119,523,716
RGD:2306714 RGD:4143515
G
Msh2 mutS homolog 2
6
11,215,951
11,274,916
RGD:2306714
G
Msh6 mutS homolog 6
6
11,644,565
11,662,389
RGD:2306714
G
Pms1 PMS1 homolog 1, mismatch repair system component
9
53,120,656
53,206,520
RGD:2306714
G
Pms2 PMS1 homolog 2, mismatch repair system component
12
12,714,394
12,738,654
RGD:2306714
Pathway Gene Annotations
Disease Annotations Associated with Genes in the mismatch repair pathway
Exo1 Breast Neoplasms , Colorectal Neoplasms , hepatocellular carcinoma Hmgb1 Acute Lung Injury , Acute-On-Chronic Liver Failure , Alzheimer's disease , amyotrophic lateral sclerosis , atherosclerosis , bilirubin metabolic disorder , Brain Injuries , Burns , Cardiomegaly , cerebral infarction , Chemical and Drug Induced Liver Injury , Chronic Allograft Dysfunction , colon adenocarcinoma , congestive heart failure , Diabetes Mellitus, Experimental , Drug-Related Side Effects and Adverse Reactions , Endotoxemia , Experimental Arthritis , Experimental Autoimmune Myocarditis , extrahepatic cholestasis , Fever , Heat Stroke , hydrocephalus , Hyperalgesia , Inflammation , Intestinal Reperfusion Injury , Kawasaki disease , Knee Osteoarthritis , leukostasis , Liver Reperfusion Injury , Lung Reperfusion Injury , Lymphatic Metastasis , malignant glioma , middle cerebral artery infarction , Multiple Organ Failure , myocardial infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , Necrosis , Neuralgia , osteoarthritis , Oxygen-Induced Retinopathy , Painful Neuropathy , Pancreatitis, Experimental, Acute , periodontitis , Premature Aging , pulmonary fibrosis , pulmonary hypertension , Reperfusion Injury , Retina Reperfusion Injury , sciatic neuropathy , Sepsis , Spinal Cord Injuries , systemic scleroderma , Systemic Vasculitis , transient cerebral ischemia , Ventilator-Induced Lung Injury Lig1 Bloom syndrome , inherited metabolic disorder , primary immunodeficiency disease , urinary bladder cancer Mlh1 cervix uteri carcinoma in situ , colon cancer , colon carcinoma , Colonic Neoplasms , colorectal cancer , Colorectal Neoplasms , Developmental Disabilities , endometrial carcinoma , Endometrial Neoplasms , gastric adenocarcinoma , Germ Cell and Embryonal Neoplasms , hereditary breast ovarian cancer syndrome , Hereditary Neoplastic Syndromes , hereditary nonpolyposis colorectal cancer type 2 , Hydatidiform Mole , lung adenocarcinoma , lung carcinoma , lymphoma , Lynch syndrome , Muir-Torre syndrome , Multiple Primary Neoplasms , Neoplasm Metastasis , ovarian cancer , Ovarian Neoplasms , Prostatic Neoplasms , renal cell carcinoma , sporadic breast cancer , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer , Uterine Cervical Neoplasms , Vulvar Neoplasms Mlh3 Breast Cancer, Familial , breast carcinoma , colon carcinoma , colorectal cancer , Colorectal Neoplasms , endometrial cancer , endometrial carcinoma , Endometrial Neoplasms , Esophageal Neoplasms , Hereditary Neoplastic Syndromes , hereditary nonpolyposis colorectal cancer type 7 , intellectual disability , leukoencephalopathy with vanishing white matter , Lynch syndrome , ventricular septal defect Msh2 ascending colon cancer , breast cancer , breast carcinoma , cervix uteri carcinoma in situ , colitis , colon cancer , colon carcinoma , colorectal cancer , Colorectal Neoplasms , Endometrial Neoplasms , Germ Cell and Embryonal Neoplasms , glioblastoma multiforme , Hereditary Neoplastic Syndromes , Huntington's disease , Hydatidiform Mole , Hydatidiform Mole, Invasive , Lynch syndrome , Lynch syndrome 1 , Muir-Torre syndrome , Neoplasm Metastasis , ovarian cancer , Ovarian Neoplasms , papillary renal cell carcinoma , prostate cancer , renal cell carcinoma , sigmoid colon cancer , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer , Urogenital Neoplasms , Uterine Cervical Neoplasms , visual epilepsy , Vulvar Neoplasms Msh3 colorectal carcinoma , Digestive System Neoplasms , endometrial cancer , endometrial carcinoma , Endometrial Neoplasms , familial adenomatous polyposis , familial adenomatous polyposis 4 , Microsatellite Instability , Prostatic Neoplasms Msh6 colon adenocarcinoma , colorectal cancer , Colorectal Neoplasms , endometrial cancer , endometrial carcinoma , Endometrial Neoplasms , Gaucher's disease , Gaucher's disease type I , genetic disease , Hereditary Neoplastic Syndromes , hereditary nonpolyposis colorectal cancer type 5 , Lynch syndrome , Lynch syndrome 1 , Macular Dystrophy, Concentric Annular , methylmalonic aciduria and homocystinuria type cblC , Microsatellite Instability , ovarian cancer , sigmoid colon cancer , Tumor Predisposition Syndrome , Turcot Syndrome Pcna adenocarcinoma , Ataxia Telangiectasia Like Disorder , Ataxia-Telangiectasia-Like Disorder 2 , brain ischemia , Brain Neoplasms , Breast Neoplasms , Chagas Cardiomyopathy , Colonic Neoplasms , Experimental Neoplasms , focal segmental glomerulosclerosis , Germ Cell and Embryonal Neoplasms , hepatoblastoma , hepatocellular carcinoma , hypothyroidism , Intimal Hyperplasia , invasive ductal carcinoma , ischemia , leiomyoma , Lewy body dementia , Liver Injury , Lung Neoplasms , Mammary Neoplasms, Experimental , mucositis , Neoplasm Metastasis , nephroblastoma , obstructive jaundice , osteoporosis , Phyllodes Tumor , psoriasis , Radiation Injuries, Experimental , renal cell carcinoma , sciatic neuropathy , seminoma , Testicular Neoplasms , transient cerebral ischemia Pms1 Colorectal Neoplasms , dermatomyositis , hereditary breast ovarian cancer syndrome , Lynch syndrome , Lynch syndrome 1 , pancreatic ductal carcinoma , Polymyositis , Prostatic Neoplasms Pms2 Brain Neoplasms , breast cancer , Burkitt lymphoma , Cafe-au-Lait Spots , colon cancer , Colonic Neoplasms , Colorectal Neoplasms , Hereditary Neoplastic Syndromes , hereditary nonpolyposis colorectal cancer type 4 , Lynch syndrome , Neoplasm Metastasis , ovarian cancer , pituitary carcinoma , precursor lymphoblastic lymphoma/leukemia , Primitive Neuroectodermal Tumors , prostate cancer , pulmonary hypertension , rhabdomyosarcoma , Supratentorial Neoplasms , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer Pold1 colon cancer , colon carcinoma , colorectal cancer , COLORECTAL CANCER 10 , Colorectal Neoplasms , Deafness , Endometrial Neoplasms , Hereditary Neoplastic Syndromes , hypogonadism , Jaw Abnormalities , lipodystrophy , Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome , Multiple Abnormalities Pold2 pleomorphic xanthoastrocytoma Pold3 Colorectal Neoplasms Rfc1 Colonic Neoplasms , osteosarcoma Rfc2 autism spectrum disorder , autistic disorder , pleomorphic xanthoastrocytoma , schizophrenia Rfc4 3MC syndrome 1 , Animal Disease Models Rpa1 Chloracne Ssbp1 Arsenic Poisoning , skin disease
3MC syndrome 1 Rfc4 Acute Lung Injury Hmgb1 Acute-On-Chronic Liver Failure Hmgb1 adenocarcinoma Pcna Alzheimer's disease Hmgb1 amyotrophic lateral sclerosis Hmgb1 Animal Disease Models Rfc4 Arsenic Poisoning Ssbp1 ascending colon cancer Msh2 Ataxia Telangiectasia Like Disorder Pcna Ataxia-Telangiectasia-Like Disorder 2 Pcna atherosclerosis Hmgb1 autism spectrum disorder Rfc2 autistic disorder Rfc2 bilirubin metabolic disorder Hmgb1 Bloom syndrome Lig1 Brain Injuries Hmgb1 brain ischemia Pcna Brain Neoplasms Pcna , Pms2 breast cancer Msh2 , Pms2 Breast Cancer, Familial Mlh3 breast carcinoma Mlh3 , Msh2 Breast Neoplasms Exo1 , Pcna Burkitt lymphoma Pms2 Burns Hmgb1 Cafe-au-Lait Spots Pms2 Cardiomegaly Hmgb1 cerebral infarction Hmgb1 cervix uteri carcinoma in situ Mlh1 , Msh2 Chagas Cardiomyopathy Pcna Chemical and Drug Induced Liver Injury Hmgb1 Chloracne Rpa1 Chronic Allograft Dysfunction Hmgb1 colitis Msh2 colon adenocarcinoma Hmgb1 , Msh6 colon cancer Mlh1 , Msh2 , Pms2 , Pold1 colon carcinoma Mlh1 , Mlh3 , Msh2 , Pold1 Colonic Neoplasms Mlh1 , Pcna , Pms2 , Rfc1 colorectal cancer Mlh1 , Mlh3 , Msh2 , Msh6 , Pold1 COLORECTAL CANCER 10 Pold1 colorectal carcinoma Msh3 Colorectal Neoplasms Exo1 , Mlh1 , Mlh3 , Msh2 , Msh6 , Pms1 , Pms2 , Pold1 , Pold3 congestive heart failure Hmgb1 Deafness Pold1 dermatomyositis Pms1 Developmental Disabilities Mlh1 Diabetes Mellitus, Experimental Hmgb1 Digestive System Neoplasms Msh3 Drug-Related Side Effects and Adverse Reactions Hmgb1 endometrial cancer Mlh3 , Msh3 , Msh6 endometrial carcinoma Mlh1 , Mlh3 , Msh3 , Msh6 Endometrial Neoplasms Mlh1 , Mlh3 , Msh2 , Msh3 , Msh6 , Pold1 Endotoxemia Hmgb1 Esophageal Neoplasms Mlh3 Experimental Arthritis Hmgb1 Experimental Autoimmune Myocarditis Hmgb1 Experimental Neoplasms Pcna extrahepatic cholestasis Hmgb1 familial adenomatous polyposis Msh3 familial adenomatous polyposis 4 Msh3 Fever Hmgb1 focal segmental glomerulosclerosis Pcna gastric adenocarcinoma Mlh1 Gaucher's disease Msh6 Gaucher's disease type I Msh6 genetic disease Msh6 Germ Cell and Embryonal Neoplasms Mlh1 , Msh2 , Pcna glioblastoma multiforme Msh2 Heat Stroke Hmgb1 hepatoblastoma Pcna hepatocellular carcinoma Exo1 , Pcna hereditary breast ovarian cancer syndrome Mlh1 , Pms1 Hereditary Neoplastic Syndromes Mlh1 , Mlh3 , Msh2 , Msh6 , Pms2 , Pold1 hereditary nonpolyposis colorectal cancer type 2 Mlh1 hereditary nonpolyposis colorectal cancer type 4 Pms2 hereditary nonpolyposis colorectal cancer type 5 Msh6 hereditary nonpolyposis colorectal cancer type 7 Mlh3 Huntington's disease Msh2 Hydatidiform Mole Mlh1 , Msh2 Hydatidiform Mole, Invasive Msh2 hydrocephalus Hmgb1 Hyperalgesia Hmgb1 hypogonadism Pold1 hypothyroidism Pcna Inflammation Hmgb1 inherited metabolic disorder Lig1 intellectual disability Mlh3 Intestinal Reperfusion Injury Hmgb1 Intimal Hyperplasia Pcna invasive ductal carcinoma Pcna ischemia Pcna Jaw Abnormalities Pold1 Kawasaki disease Hmgb1 Knee Osteoarthritis Hmgb1 leiomyoma Pcna leukoencephalopathy with vanishing white matter Mlh3 leukostasis Hmgb1 Lewy body dementia Pcna lipodystrophy Pold1 Liver Injury Pcna Liver Reperfusion Injury Hmgb1 lung adenocarcinoma Mlh1 lung carcinoma Mlh1 Lung Neoplasms Pcna Lung Reperfusion Injury Hmgb1 Lymphatic Metastasis Hmgb1 lymphoma Mlh1 Lynch syndrome Mlh1 , Mlh3 , Msh2 , Msh6 , Pms1 , Pms2 Lynch syndrome 1 Msh2 , Msh6 , Pms1 Macular Dystrophy, Concentric Annular Msh6 malignant glioma Hmgb1 Mammary Neoplasms, Experimental Pcna Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome Pold1 methylmalonic aciduria and homocystinuria type cblC Msh6 Microsatellite Instability Msh3 , Msh6 middle cerebral artery infarction Hmgb1 mucositis Pcna Muir-Torre syndrome Mlh1 , Msh2 Multiple Abnormalities Pold1 Multiple Organ Failure Hmgb1 Multiple Primary Neoplasms Mlh1 myocardial infarction Hmgb1 Myocardial Ischemia Hmgb1 Myocardial Reperfusion Injury Hmgb1 Necrosis Hmgb1 Neoplasm Metastasis Mlh1 , Msh2 , Pcna , Pms2 nephroblastoma Pcna Neuralgia Hmgb1 obstructive jaundice Pcna osteoarthritis Hmgb1 osteoporosis Pcna osteosarcoma Rfc1 ovarian cancer Mlh1 , Msh2 , Msh6 , Pms2 Ovarian Neoplasms Mlh1 , Msh2 Oxygen-Induced Retinopathy Hmgb1 Painful Neuropathy Hmgb1 pancreatic ductal carcinoma Pms1 Pancreatitis, Experimental, Acute Hmgb1 papillary renal cell carcinoma Msh2 periodontitis Hmgb1 Phyllodes Tumor Pcna pituitary carcinoma Pms2 pleomorphic xanthoastrocytoma Pold2 , Rfc2 Polymyositis Pms1 precursor lymphoblastic lymphoma/leukemia Pms2 Premature Aging Hmgb1 primary immunodeficiency disease Lig1 Primitive Neuroectodermal Tumors Pms2 prostate cancer Msh2 , Pms2 Prostatic Neoplasms Mlh1 , Msh3 , Pms1 psoriasis Pcna pulmonary fibrosis Hmgb1 pulmonary hypertension Hmgb1 , Pms2 Radiation Injuries, Experimental Pcna renal cell carcinoma Mlh1 , Msh2 , Pcna Reperfusion Injury Hmgb1 Retina Reperfusion Injury Hmgb1 rhabdomyosarcoma Pms2 schizophrenia Rfc2 sciatic neuropathy Hmgb1 , Pcna seminoma Pcna Sepsis Hmgb1 sigmoid colon cancer Msh2 , Msh6 skin disease Ssbp1 Spinal Cord Injuries Hmgb1 sporadic breast cancer Mlh1 Supratentorial Neoplasms Pms2 systemic scleroderma Hmgb1 Systemic Vasculitis Hmgb1 Testicular Neoplasms Pcna transient cerebral ischemia Hmgb1 , Pcna Tumor Predisposition Syndrome Mlh1 , Msh2 , Msh6 , Pms2 Turcot Syndrome Mlh1 , Msh2 , Msh6 , Pms2 urinary bladder cancer Lig1 , Mlh1 , Msh2 , Pms2 Urogenital Neoplasms Msh2 Uterine Cervical Neoplasms Mlh1 , Msh2 Ventilator-Induced Lung Injury Hmgb1 ventricular septal defect Mlh3 visual epilepsy Msh2 Vulvar Neoplasms Mlh1 , Msh2
