Mutator genes, cell genome stability

Mutator genes
DNA repair genes control the stability of the cell genome. They are responsible for repairing DNA damage.


 * 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
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
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 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.

Related articles

 * Mutation
 * Tumor suppressor genes
 * Oncogenes
 * Chromosomal aberrations in the etiology of neoplasms