Genome instability - Wikipedia, the free encyclopedia

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Genome instability
From Wikipedia, the free encyclopedia

Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability is central to carcinogenesis[1] but also is a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage[2] can be one source of genome instability since DNA damages can cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation. Another source of genome instability may be epigenetic reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very frequent, occurring on average more than 10,000 times a day in the genomes of human cells, epigenetically reduced DNA repair is likely an important source of genome instability.

Contents
1 The usual genome situation 2 Genome instability in neuronal and neuromuscular disease 3 Genome instability in cancer 4 References

The usual genome situation

Usually, all cells in an individual in a given species (plant or animal) show a constant number of chromosomes, which constitute what is known as the karyotype defining this species (see also List of number of chromosomes of various organisms), although some species present a very high karyotypic variability. Sometimes, in a species with a stable karyotype, random variations that modify the normal number of chromosomes may be observed. In other cases, there are structural alterations (chromosomal translocations, deletions ...) that modify the standard chromosomal complement. In these cases, it is indicated that the affected organism presents genome instability (also genetic instability, or even chromosomic instability). The process of genome instability often leads to a situation of aneuploidy, in which the cells present a chromosomic number that is either higher or lower than the normal complement for the species.

Genome instability in neuronal and neuromuscular disease

Of about 200 neurological and neuromuscular disorders, 15 have a clear link to an inherited or acquired defect in one of the DNA repair pathways or excessive genotoxic oxidative stress.[3][4] Five of them (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down's syndrome, and triple-A syndrome) have a defect in the DNA nucleotide excision repair pathway. Six (spinocerebellar ataxia with axonal neuropathy-1, Huntingtons disease, Alzheimers disease, Parkinsons disease, Down's syndrome and amyotrophic lateral sclerosis) seem to result from increased oxidative stress, and the inability of the base excision repair pathway to

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handle the damage to DNA that this causes. Four of them (Huntingtons disease, various spinocerebellar ataxias, Friedreichs ataxia and myotonic dystrophy types 1 and 2) often have an unusual expansion of repeat sequences in DNA, likely attributable to genome instability. Four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimers disease) are defective in genes involved in repairing DNA double-strand breaks. Overall, it seems that oxidative stress is a major cause of genomic instability in the brain. A particular neurological disease arises when a pathway that normally prevents oxidative stress is deficient, or a DNA repair pathway that normally repairs damage caused by oxidative stress is deficient.

Genome instability in cancer

In cancer, genome instability can occur prior to or as a consequence of transformation.[5] Genome instability can refer to the accumulation of extra copies of DNA or chromosomes, chromosomal translocations, chromosomal inversions, chromosome deletions, single-strand breaks in DNA, double-strand breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. Situations of genome instability (as well as aneuploidy) are common in cancer cells, and they are considered a "trademark" for these cells. It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors,[6] with most often about 15 "driver mutations" and about 60 "passenger mutations".[7] Any genetic or epigenetic lesion increasing the mutation rate will have as a consequence an increase in the acquisition of new mutations, increasing then the probability to develop a tumor.[8] During the process of tumorogenesis, it is known that diploid cells acquire mutations in genes responsible for maintaining genome integrity (caretaker genes), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes).[9] Genetic instability can originate due to deficiencies in DNA repair, or due to loss or gain of chromosomes, or due to large scale chromosomal reorganizations. Losing genetic stability will favour tumor development, because it favours the generation of mutants that can be selected by the environment.[10] The basic underlying cause of cancer is DNA damage.[11] If exogenous DNA damage is high, such as from genotoxic tobacco smoke agents (acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene )[12] these damages may be converted into mutations by inaccurate translesion synthesis or inaccurate DNA repair. However, DNA damages may also be converted into epigenetic alterations during DNA repair.[13][14][15] A mutation or an epimutation in a DNA repair gene would cause a mutator phenotype,[1] leading to an increasing frequency of mutations, and thereby an increasing risk of a carcinogenic combination of mutations/epimutations. In addition, once a mutation or an epimutation causes a loss of DNA repair capacity, then even naturally occurring endogenous DNA damages, which are very frequent, occurring on average more than 10,000 times a day in the genomes of human cells, could become a source of further mutation or epimutation. In somatic cells, deficiencies in DNA repair sometimes arise by mutations in DNA repair genes, but much more often are due to epigenetic reductions in expression of DNA repair genes. Thus, in a sequence of 113 colorectal cancers, only four had somatic missense mutations in the DNA repair gene MGMT, while the majority of these cancers had reduced MGMT expression due to methylation of the MGMT promoter region. Five reports, listed in the article Epigenetics (see section DNA repair epigenetics in cancer) presented evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region. Similarly, for 119 cases of colorectal cancers classified as mismatch repair deficient and lacking DNA repair gene PMS2 expression, Pms2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2

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expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[16] The other 10 cases of loss of PMS2 expression were likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[17] In the article Epigenetics (see section DNA repair epigenetics in cancer), there is a partial listing of epigenetic deficiencies found in DNA repair genes in sporadic cancers. These include frequencies of between 13%-100% of epigenetic defects in genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM located in cancers including breast, ovarian, colorectal and head and neck. Two or three epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 were shown to occur simultaneously in the majority of the 49 colon cancers evaluated.[18] Deficiencies in DNA repair genes cause increased mutation rates.[19][20][21] Also, chromosomal rearrangements and aneuploidy increase in humans defective in DNA repair gene BLM.[22] This indicates that deficiency in DNA repair causes genome instability.

References
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