Mutator genes, cell genome stability
Mutator genes[edit | edit source]
- Mutation or inactivation of these geneslead to the accumulation and maintenance of mutations in the cell and the instability of the genome.
- Increased frequency and accumulation of mutations in the cell is one of the causes of malignant transformation.
- The products of these genes are involved in the repair mechanisms of damaged DNA.
- Mutator genes, unlike oncogenes and tumor suppressor genes, do not give a cell the ability to proliferate uncontrollably by itself. Thus, mutation of mutator genes leads to an increased frequency (100-1000-fold) of mutated oncogenes and tumor suppressor genes.
Genes enabling the excisional correction process[edit | edit source]
These include genes whose products cause excision. Their recessive mutations cause a condition called xeroderma pigmentosum and Cockayn's syndrome, which are precancerous lesions with an increased susceptibility to skin cancers induced by UV exposure
"Mismatch" repair genes - mutations in Mismatch Repair genes[edit | edit source]
Another group of mutator genes. The encoded proteins correct the base misalignment during DNA replication (but not complementary)
- The manifestation of mutations of these genes is instability at the nucleotide level, instability of microsatellite loci (MIN) - microsatellite instability (incorrect base pairing causes changes in the length of microsatellite sequences - their lengthening or shortening).
- Instability of microsatellite sequence lengths leads to replication errors.
- Mutations are recessive.
- Microsatellite sequences are distributed throughout the genome and are inherited in length. They are repetitive sequences of dinucleotides or trinucleotides, there are 50,000-100,000 (CA) n repeats in the human genome.
Germline mutations, especially hMSH2 (human MutS homolog 2), hMLH1, hPMSI and hPMS2 genes are the basis of hereditary non-polyposis colorectal cancer (HNPCC) – inheritedautosomal dominantly, familial occurrence is considered to affect 3 or more family members with a The kinship coefficient 0,5 and an incidence disease before the age of 50.
- Familial occurrence of HNPCC accompanied only by the finding of cancer of the colon or rectum (so-called Lynch syndrome I ).
- In addition, about 30% of HNPCC patients develop carcinomas in other organs (endometrium, pancreas, stomach, urinary tract). This is the so-called Lynch syndrome II.
- The HMSH2 (chrom. 2p15-p22), hMLH1 (chrom. 3p21.3), hPMSI (2q31-33) and hPMS2 (chrom. 7p22) genes are responsible for correcting base mismatches (MMRs). Their mutations predispose to Lynch syndrome.
The instability of microsatellites has been described as a characteristic phenotypic manifestation in other tumors – breast and lung cancers, GIT tumors, endometrium, and meningiomas. Defects of the DNA-repair mechanism contribute to the accumulation of genetic defects, support the progression of malignantly transformed cells.
Examples of investigated mutator genes
|hMSH2||HNPCC, type 1, ovarian tumors, glioblastomas, T-cell lymphomas|
|hMSH6||HNPCC, type 5, ovarian tumors, endometrial cancer|
|hMLH||HNPCC, type 2, Turcott syndrome accompanied by glioblastomas and leukemias|
|hPMS1||the protein encoded by this gene forms heterodimers with the protein encoded by the hMLH1 gene, has been detected in mutated form in some HNPCCs|
|hPMS2||HNPCC, type 4, Turcott syndrome accompanied by glioblastomas|
Turcott syndrome is clinically characterized as a coincidence of hereditary primary colon tumors (FAP or HNPCC) with tumors of the central nervous system or leukemia.
Defects of the DNA-repair mechanism contribute to the accumulation of genetic defects, support the progression of malignantly transformed cells.
Links[edit | edit source]
Related articles[edit | edit source]
References[edit | edit source]
- ŠTEFÁNEK, Jiří. Medicína, nemoci, studium na 1. LF UK [online]. [cit. 11.02.2010]. <http://www.stefajir.cz>.