View source for Mutator genes, stability of the cell genome

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==Mutator Genes==
DNA repair genes control the stability of the cell's [[genome]]. They are responsible for repair of damage (error correction) [[DNA (nucleic acid)|DNA]].

* [[Mutation]] or inactivation of these [[Gene|genes]] leads to the accumulation and maintenance of mutations in the cell and genome instability.
* Increased frequency and accumulation of mutations in the cell is one of the causes of malignant transformation.
* The products of these genes are used in the repair mechanisms of damaged DNA.
* Mutator genes, unlike [[(Proto)oncogenes|oncogenes]] and [[tumor suppressor genes|tumor suppressor genes]], do not provide the cell with the ability to proliferate uncontrollably by themselves. Thus, the mutation of mutator genes leads to an increased frequency (100–1000 times) of mutated oncogenes and tumor suppressor genes

===Genes enabling the excision repair process===
These include genes whose products ensure the cutting out of a damaged section of DNA (excision). Their recessive mutation causes diseases called [[xeroderma pigmentosum]] and [[Cockayne syndrome]], which are [[Precancerous condition|pre-cancers]] with increased susceptibility to [[Skin tumors|skin cancers]] induced by [[Ultraviolet radiation (biophysics)|UV-radiation]] exposure.


===“Mismatch” repair genes - mutation of genes for repairing faulty base pairing (Mismatch Repair genes)===
Another group of mutator genes. Encoded proteins correct base misplacement during DNA replication (but not complementary).

* A manifestation of mutations of these genes is instability at the nucleotide level, instability of the length of microsatellite loci (MIN) - microsatellite instability (incorrect base pairing causes changes in the length of microsatellite sequences - their lengthening or shortening).
* Length instability of microsatellite sequences leads to replication errors.
* Mutations are recessive in nature.
* Microsatellite sequences are distributed throughout the genome, their length is heritable. They are repetitive sequences of dinucleotides or trinucleotides, 50,000–100,000 (CA)n repeats occur in the human genome.

Germline mutations in particular hMSH2 (human MutS homolog 2), hMLH1, hPMSI and hPMS2 genes underlie '''hereditary nonpolyposis colorectal cancer (HNPCC)''' - inherited [[autosomal dominant inheritance|autosomal dominant]], it is considered a familial occurrence affected 3 or more family members with a [[affinity coefficient]] of 0.5 and with the occurrence of the disease before the age of 50.

* Familial occurrence of HNPCC accompanied only by the finding of colon or rectal cancer so-called '''[[Lynch syndrome|Lynch syndrome I]]'''.
* About 30% of HNPCC patients also develop cancers in other organs (endometrium, pancreas, stomach, urinary tract). This is the so-called ''Lynch syndrome II''.
* HMSH2 (chrom. 2p15-p22), hMLH1 (chrom. 3p21.3), hPMSI (2q31–33) and hPMS2 (chrom. 7p22) genes are responsible for base mismatch repair (MMR). Their mutations predispose to Lynch syndrome.


Instability of microsatellites has been described as a characteristic [[Phenotype|phenotypic]] manifestation in other tumors - [[Breast Tumors|breast cancer]] and [[Lung|lung]], GIT tumors, endometrium, meningiomas. Defects in the DNA-repair mechanism contribute to the accumulation of genetic defects, promote the progression of malignantly transformed cells.

'''Examples''' of mutator genes explored
{| class="wikitable"
|hMSH2
|HNPCC, type 1, ovarian tumors, glioblastomas, T-cell lymphomas
|-
|hMSH6
|HNPCC, type 5, ovarian tumors, endometrial carcinoma
|-
|hMLH
|HNPCC, type 2, Turcott syndrome accompanied by the occurrence of glioblastomas and leukemia
|-
|hPMS1
|the protein encoded by this gene forms heterodimers with the protein encoded by the hMLH1 gene, it has been detected in a mutated form in some HNPCC
|-
|hPMS2
|HNPCC, type 4, Turcott syndrome accompanied by the occurrence of glioblastomas
|}
'''Turcott syndrome''' is clinically characterized as the coincidence of the hereditary occurrence of primary colon tumors (FAP or HNPCC) with tumors of the central nervous system, or with leukemia

·       '''defects in the DNA-repair mechanism''' contribute to the accumulation of genetic defects, promote the '''progression''' of malignantly transformed cells

==Links==
=== Source ===
* [[ws:Mutátorové geny, stabilita buněčného genomu]]
===Related Articles===

*[[Mutation]]
*[[Tumor suppressor genes]]
*[[Oncogenes]]
*[[Chromosome aberrations in the etiology of neoplasia]]

===Source===

* {{Cite
|type = web
|surname1 = Štefánek
|name1 = Jiří
|source_name = Medicine, diseases, studies at the 1st Faculty of Medicine, UK
|cited =2010-02-11
|url = http://www.stefajir.cz
}}

[[Category:Genetics]]
[[Category:Pathophysiology]]
[[Category:Pathobiochemistry]]
[[Category:Oncology]]