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 Hmgb1 Acute Lung Injury , Acute-On-Chronic Liver Failure , Adenocarcinoma, Colon , Aging, Premature , Alzheimer's Disease , amyotrophic lateral sclerosis , Arthritis, Experimental , atherosclerosis , Brain Injuries , Burns , Cardiomegaly , Cerebral Infarction , Chemical and Drug Induced Liver Injury , Cholestasis, Extrahepatic , Chronic Allograft Dysfunction , diabetes mellitus, experimental , Drug-Related Side Effects and Adverse Reactions , Endotoxemia , esophageal squamous cell carcinoma , experimental autoimmune myocarditis , Fever , glioma , Heart Failure , Heat Stroke , Hydrocephalus , Hyperalgesia , Hyperbilirubinemia , Infarction, Middle Cerebral Artery , Inflammation , Intestinal Reperfusion Injury , Liver Reperfusion Injury , Lung Reperfusion Injury , Lymphatic Metastasis , Mucocutaneous Lymph Node Syndrome , Multiple Organ Failure , Myocardial Infarction , Myocardial Ischemia , Myocardial Reperfusion Injury , Necrosis , Neuralgia , Neuropathy, Painful , Osteoarthritis , Osteoarthritis, Knee , Oxygen-Induced Retinopathy , Pancreatitis, Experimental, Acute , Periodontitis , Pulmonary Fibrosis , pulmonary hypertension , Reperfusion Injury , Retina Reperfusion Injury , Sciatic Neuropathy , Scleroderma, Systemic , Sepsis , Spinal Cord Injuries , Systemic Vasculitis , transient cerebral ischemia , Ventilator-Induced Lung Injury Lig1 Bloom Syndrome , Immunologic Deficiency Syndromes , inherited metabolic disorder , urinary bladder cancer Mlh1 ADENOCARCINOMA OF STOMACH , Breast Neoplasms , Carcinoma, Renal Cell , cervical intraepithelial neoplasia , colon cancer , Colonic Neoplasms , Colorectal Cancer, Hereditary Nonpolyposis, Type 1 , Colorectal Neoplasms , Developmental Disabilities , endometrial carcinoma , Endometrial Neoplasms , hereditary nonpolyposis colorectal neoplasm , Hydatidiform Mole , lung adenocarcinoma , Lung Neoplasms , lymphoma , Lynch Syndrome II , Muir-Torre syndrome , Neoplasm Metastasis , Neoplasms, Germ Cell and Embryonal , Neoplasms, Multiple Primary , Neoplastic Syndromes, Hereditary , ovarian cancer , Ovarian Neoplasms , prostatic neoplasms , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer , uterine cervical neoplasms , Vulvar Neoplasms Mlh3 breast cancer, familial , breast carcinoma , colon cancer , colon carcinoma , Colonic Neoplasms , colorectal cancer , Colorectal Cancer, Hereditary Nonpolyposis, Type 7 , Colorectal Neoplasms , endometrial carcinoma , Endometrial Neoplasms , Esophageal Neoplasms , Heart Septal Defects, Ventricular , hereditary nonpolyposis colorectal neoplasm , Leukoencephalopathies , Neoplastic Syndromes, Hereditary Msh2 Breast Neoplasms , Carcinoma, Renal Cell , cervical intraepithelial neoplasia , Colitis , colorectal cancer , Colorectal Cancer, Hereditary Nonpolyposis, Type 1 , Colorectal Neoplasms , Endometrial Neoplasms , hereditary nonpolyposis colorectal neoplasm , Huntington's Disease , Hydatidiform Mole , Hydatidiform Mole, Invasive , Muir-Torre syndrome , Neoplasm Metastasis , Neoplasms, Germ Cell and Embryonal , Neoplastic Syndromes, Hereditary , ovarian cancer , Ovarian Neoplasms , prostatic neoplasms , Seizures , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer , Urogenital Neoplasms , uterine cervical neoplasms , Vulvar Neoplasms Msh3 Adenomatous Polyposis Coli , Colorectal Neoplasms , Digestive System Neoplasms , endometrial cancer , endometrial carcinoma , Endometrial Neoplasms , familial adenomatous polyposis 4 , lung adenocarcinoma , Microsatellite Instability , prostatic neoplasms Msh6 colorectal cancer , Colorectal Cancer, Hereditary Nonpolyposis, Type 1 , Colorectal Cancer, Hereditary Nonpolyposis, Type 5 , Colorectal Neoplasms , endometrial carcinoma , Endometrial Neoplasms , Gaucher Disease , hereditary nonpolyposis colorectal neoplasm , lung adenocarcinoma , Microsatellite Instability , Neoplastic Syndromes, Hereditary , ovarian cancer , Ovarian Neoplasms , Tumor Predisposition Syndrome , Turcot Syndrome Pcna adenocarcinoma , ataxia telangiectasia like disorder , ataxia-telangiectasia-like disorder 2 , Brain Ischemia , Brain Neoplasms , Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Hepatocellular , Carcinoma, Renal Cell , Chagas Cardiomyopathy , Colonic Neoplasms , focal segmental glomerulosclerosis , hepatoblastoma , Hypothyroidism , Intimal Hyperplasia , Ischemia , Jaundice, Obstructive , Leiomyoma , Lewy body dementia , Liver Injury , Lung Neoplasms , Mammary Neoplasms, Experimental , Mucositis , Neoplasm Metastasis , Neoplasms, Experimental , Neoplasms, Germ Cell and Embryonal , Osteoporosis , Phyllodes Tumor , psoriasis , Radiation Injuries, Experimental , Sciatic Neuropathy , Seminoma , Testicular Neoplasms , transient cerebral ischemia , Wilms tumor Pms1 Colorectal Cancer, Hereditary Nonpolyposis, Type 1 , Colorectal Neoplasms , dermatomyositis , hereditary nonpolyposis colorectal neoplasm , pancreatic ductal carcinoma , Polymyositis Pms2 Brain Neoplasms , Breast Neoplasms , Cafe-au-Lait Spots , Colonic Neoplasms , Colorectal Cancer, Hereditary Nonpolyposis, Type 1 , Colorectal Cancer, Hereditary Nonpolyposis, Type 4 , Colorectal Neoplasms , hereditary nonpolyposis colorectal neoplasm , Neoplasm Metastasis , Neoplastic Syndromes, Hereditary , Neuroectodermal Tumors, Primitive , Ovarian Neoplasms , prostatic neoplasms , Rhabdomyosarcoma , supratentorial neoplasms , Tumor Predisposition Syndrome , Turcot Syndrome , urinary bladder cancer Pold1 Abnormalities, Multiple , colon cancer , colon carcinoma , Colonic Neoplasms , colorectal cancer , COLORECTAL CANCER 10 , Colorectal Neoplasms , Deafness , Endometrial Neoplasms , Hypogonadism , Jaw Abnormalities , Lipodystrophy , Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome , Neoplastic Syndromes, Hereditary Pold2 Pleomorphic Xanthoastrocytoma Pold3 Colorectal Neoplasms Rfc1 Colonic Neoplasms , Osteosarcoma Rfc2 Autism Spectrum Disorder , Pleomorphic Xanthoastrocytoma Rfc4 Disease Models, Animal , lung adenocarcinoma Rpa1 Chloracne Ssbp1 Arsenic Poisoning , Skin Diseases
Abnormalities, Multiple Pold1 Acute Lung Injury Hmgb1 Acute-On-Chronic Liver Failure Hmgb1 adenocarcinoma Pcna ADENOCARCINOMA OF STOMACH Mlh1 Adenocarcinoma, Colon Hmgb1 Adenomatous Polyposis Coli Msh3 Aging, Premature Hmgb1 Alzheimer's Disease Hmgb1 amyotrophic lateral sclerosis Hmgb1 Arsenic Poisoning Ssbp1 Arthritis, Experimental Hmgb1 ataxia telangiectasia like disorder Pcna ataxia-telangiectasia-like disorder 2 Pcna atherosclerosis Hmgb1 Autism Spectrum Disorder Rfc2 Bloom Syndrome Lig1 Brain Injuries Hmgb1 Brain Ischemia Pcna Brain Neoplasms Pcna , Pms2 breast cancer, familial Mlh3 breast carcinoma Mlh3 Breast Neoplasms Exo1 , Mlh1 , Msh2 , Pcna , Pms2 Burns Hmgb1 Cafe-au-Lait Spots Pms2 Carcinoma, Ductal, Breast Pcna Carcinoma, Hepatocellular Pcna Carcinoma, Renal Cell Mlh1 , Msh2 , Pcna Cardiomegaly Hmgb1 Cerebral Infarction Hmgb1 cervical intraepithelial neoplasia Mlh1 , Msh2 Chagas Cardiomyopathy Pcna Chemical and Drug Induced Liver Injury Hmgb1 Chloracne Rpa1 Cholestasis, Extrahepatic Hmgb1 Chronic Allograft Dysfunction Hmgb1 Colitis Msh2 colon cancer Mlh1 , Mlh3 , Pold1 colon carcinoma Mlh3 , Pold1 Colonic Neoplasms Mlh1 , Mlh3 , Pcna , Pms2 , Pold1 , Rfc1 colorectal cancer Mlh3 , Msh2 , Msh6 , Pold1 COLORECTAL CANCER 10 Pold1 Colorectal Cancer, Hereditary Nonpolyposis, Type 1 Mlh1 , Msh2 , Msh6 , Pms1 , Pms2 Colorectal Cancer, Hereditary Nonpolyposis, Type 4 Pms2 Colorectal Cancer, Hereditary Nonpolyposis, Type 5 Msh6 Colorectal Cancer, Hereditary Nonpolyposis, Type 7 Mlh3 Colorectal Neoplasms Exo1 , Mlh1 , Mlh3 , Msh2 , Msh3 , Msh6 , Pms1 , Pms2 , Pold1 , Pold3 Deafness Pold1 dermatomyositis Pms1 Developmental Disabilities Mlh1 diabetes mellitus, experimental Hmgb1 Digestive System Neoplasms Msh3 Disease Models, Animal Rfc4 Drug-Related Side Effects and Adverse Reactions Hmgb1 endometrial cancer Msh3 endometrial carcinoma Mlh1 , Mlh3 , Msh3 , Msh6 Endometrial Neoplasms Mlh1 , Mlh3 , Msh2 , Msh3 , Msh6 , Pold1 Endotoxemia Hmgb1 Esophageal Neoplasms Mlh3 esophageal squamous cell carcinoma Hmgb1 experimental autoimmune myocarditis Hmgb1 familial adenomatous polyposis 4 Msh3 Fever Hmgb1 focal segmental glomerulosclerosis Pcna Gaucher Disease Msh6 glioma Hmgb1 Heart Failure Hmgb1 Heart Septal Defects, Ventricular Mlh3 Heat Stroke Hmgb1 hepatoblastoma Pcna hereditary nonpolyposis colorectal neoplasm Mlh1 , Mlh3 , Msh2 , Msh6 , Pms1 , Pms2 Huntington's Disease Msh2 Hydatidiform Mole Mlh1 , Msh2 Hydatidiform Mole, Invasive Msh2 Hydrocephalus Hmgb1 Hyperalgesia Hmgb1 Hyperbilirubinemia Hmgb1 Hypogonadism Pold1 Hypothyroidism Pcna Immunologic Deficiency Syndromes Lig1 Infarction, Middle Cerebral Artery Hmgb1 Inflammation Hmgb1 inherited metabolic disorder Lig1 Intestinal Reperfusion Injury Hmgb1 Intimal Hyperplasia Pcna Ischemia Pcna Jaundice, Obstructive Pcna Jaw Abnormalities Pold1 Leiomyoma Pcna Leukoencephalopathies Mlh3 Lewy body dementia Pcna Lipodystrophy Pold1 Liver Injury Pcna Liver Reperfusion Injury Hmgb1 lung adenocarcinoma Mlh1 , Msh3 , Msh6 , Rfc4 Lung Neoplasms Mlh1 , Pcna Lung Reperfusion Injury Hmgb1 Lymphatic Metastasis Hmgb1 lymphoma Mlh1 Lynch Syndrome II Mlh1 Mammary Neoplasms, Experimental Pcna Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome Pold1 Microsatellite Instability Msh3 , Msh6 Mucocutaneous Lymph Node Syndrome Hmgb1 Mucositis Pcna Muir-Torre syndrome Mlh1 , Msh2 Multiple Organ Failure Hmgb1 Myocardial Infarction Hmgb1 Myocardial Ischemia Hmgb1 Myocardial Reperfusion Injury Hmgb1 Necrosis Hmgb1 Neoplasm Metastasis Mlh1 , Msh2 , Pcna , Pms2 Neoplasms, Experimental Pcna Neoplasms, Germ Cell and Embryonal Mlh1 , Msh2 , Pcna Neoplasms, Multiple Primary Mlh1 Neoplastic Syndromes, Hereditary Mlh1 , Mlh3 , Msh2 , Msh6 , Pms2 , Pold1 Neuralgia Hmgb1 Neuroectodermal Tumors, Primitive Pms2 Neuropathy, Painful Hmgb1 Osteoarthritis Hmgb1 Osteoarthritis, Knee Hmgb1 Osteoporosis Pcna Osteosarcoma Rfc1 ovarian cancer Mlh1 , Msh2 , Msh6 Ovarian Neoplasms Mlh1 , Msh2 , Msh6 , Pms2 Oxygen-Induced Retinopathy Hmgb1 pancreatic ductal carcinoma Pms1 Pancreatitis, Experimental, Acute Hmgb1 Periodontitis Hmgb1 Phyllodes Tumor Pcna Pleomorphic Xanthoastrocytoma Pold2 , Rfc2 Polymyositis Pms1 prostatic neoplasms Mlh1 , Msh2 , Msh3 , Pms2 psoriasis Pcna Pulmonary Fibrosis Hmgb1 pulmonary hypertension Hmgb1 Radiation Injuries, Experimental Pcna Reperfusion Injury Hmgb1 Retina Reperfusion Injury Hmgb1 Rhabdomyosarcoma Pms2 Sciatic Neuropathy Hmgb1 , Pcna Scleroderma, Systemic Hmgb1 Seizures Msh2 Seminoma Pcna Sepsis Hmgb1 Skin Diseases Ssbp1 Spinal Cord Injuries Hmgb1 supratentorial neoplasms Pms2 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 Vulvar Neoplasms Mlh1 , Msh2 Wilms tumor Pcna
