Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Escherichia coli methyl-directed mismatch repair eliminates premutagenic lesions that arise via DNA biosynthetic errors; components of the repair system also block ectopic recombination between diverged DNA sequences. A mismatch-dependent, methyl-directed excision reaction that accounts for function of the system in replication fidelity has been reconstituted in a purified system dependent on ten activities. The reaction displays a broad specificity for mismatched base pairs and is characterized by an unusual bidirectional excision capability. Human cell nuclear extracts support strand-specific mismatch correction in a reaction that is similar to bacterial repair, with respect to both mismatch specificity and unusual features of mechanism. Like the bacterial system, the human pathway also functions in mutation avoidance because several classes of mutator human cells are deficient in the reaction. These include an alkylation-tolerance cell line that is resistant to the cytotoxic action of N-methyl-N'-nitro-nitrosoguanidine, as well as hypermutable RER+ tumour cells such as those associated with hereditary non-polyposis colon cancer. In vitro experiments indicate that the human repair reaction is dependent on at least six activities, excluding DNA ligase, and that distinct defects in the system can lead to the RER+ phenotype.
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PMID:Mismatch repair, genetic stability and tumour avoidance. 774 60

Human leukocyte antigen (HLA) class I expression defects frequently occur in colorectal cancers bearing mismatch repair (MMR) deficiencies and are interpreted as immune evasion mechanisms to avoid cancer cell recognition and elimination by the immune system. MMR-deficient tumours are thought to be more prone to lose HLA class I expression, due to their frequent generation of aberrant peptides which can stimulate a cytotoxic T-cell-mediated response. MUTYH-associated polyposis (MAP) is a colorectal cancer syndrome caused by defects in the MUTYH DNA repair enzyme. Impairment of MUTYH activity could lead to a surplus of mutated peptides which would be presented to cytotoxic T-cells through the HLA class I molecules. We have studied the frequency of HLA class I expression defects in MAP carcinomas and have compared it to those observed in MMR-deficient and -proficient colorectal tumours. Immunohistochemical detection of the expression of HLA class I, beta2-microglobulin (beta2m), and antigen-processing machinery molecules was performed in 37 primary MAP carcinomas and nine metastases resected from 29 MAP patients. Furthermore, we sequenced the beta2m, TAP1, and TAP2 genes. Defects in HLA class I expression were detected in 65% of primary MAP carcinomas, affecting 72% of patients. HLA class I expression abnormalities were often concomitant with beta2m expression loss and mutations in the beta2m gene. Loss of HLA class I expression is thus a frequent event in MAP carcinomas, similarly to MMR-deficient colorectal tumours. The extensive mutagenic background of these tumours most likely triggers a strong selective pressure, exerted by the immune system on the tumour, which favours the outgrowth of tumour cell clones with an immune evasive phenotype. Our data provide additional evidence for a link between DNA repair deficiencies and altered HLA class I phenotypes in colorectal cancer.
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PMID:MUTYH-associated polyposis carcinomas frequently lose HLA class I expression - a common event amongst DNA-repair-deficient colorectal cancers. 1946 19

MutY is a glycosylase known for its role in DNA base excision repair (BER). It is critically important in the prevention of DNA mutations derived from 7,8-dihydro-8-oxoguanine (8-oxoG), which are the major lesions resulting from guanine oxidation. MutY has been described as a DNA repair enzyme in the GO system responsible for removing adenine residues misincorporated in 8-oxoG:A mispairs, avoiding G:C to T:A mutations. Further studies have shown that this enzyme binds to other mispairs, interacts with several enzymes, avoids different transversions/transitions in DNA, and is involved in different repair pathways. Additional activities have been reported for MutY, such as the repair of replication errors in newly synthesized DNA strands through its glycosylase activity. Moreover, MutY is a highly conserved enzyme present in several prokaryotic and eukaryotic organisms. MutY defects are associated with a hereditary colorectal cancer syndrome termed MUTYH-associated polyposis (MAP). Here, we have reviewed the roles of MutY in the repair of mispaired bases in DNA as well as its activities beyond the GO system.
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PMID:MutY-glycosylase: an overview on mutagenesis and activities beyond the GO system. 2577 31

The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]+, with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster.
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PMID:A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster. 2991 46