194:
chemically more unstable than double-stranded DNA. During elongation of transcription, supercoiling can occur behind an elongating RNA polymerase, leading to single-stranded breaks. When the coding strand is single-stranded, it can also hybridize with itself, creating DNA secondary structures that can compromise replication. In E. coli, when attempting to transcribe GAA triplets such as those found in
Friedrich's ataxia, the resulting RNA and template strand can form mismatched loops between different repeats, leaving the complementary segment in the coding strand available to form its own loops which impede replication. Furthermore, replication of DNA and transcription of DNA are not temporally independent; they can occur at the same time and lead to collisions between the replication fork and RNA polymerase complex. In S. cerevisiae, Rrm3 helicase is found at highly transcribed genes in the yeast genome, which is recruited to stabilize a stalling replication fork as described above. This suggests that transcription is an obstacle to replication, which can lead to increased stress in the chromatin spanning the short distance between the unwound replication fork and transcription start site, potentially causing single-stranded DNA breaks. In yeast, proteins act as barriers at the 3' of the transcription unit to prevent further travel of the DNA replication fork.
181:
of mutations, such as DNA-repeat expansion. Rare fragile sites can lead to genetic disease such as fragile X mental retardation syndrome, myotonic dystrophy, Friedrich's ataxia, and
Huntington's disease, most of which are caused by expansion of repeats at the DNA, RNA, or protein level. Although, seemingly harmful, these common fragile sites are conserved all the way to yeast and bacteria. These ubiquitous sites are characterized by trinucleotide repeats, most commonly CGG, CAG, GAA, and GCN. These trinucleotide repeats can form into hairpins, leading to difficulty of replication. Under
185:, such as defective machinery or further DNA damage, DNA breaks and gaps can form at these fragile sites. Using a sister chromatid as repair is not a fool-proof backup as the surrounding DNA information of the n and n+1 repeat is virtually the same, leading to copy number variation. For example, the 16th copy of CGG might be mapped to the 13th copy of CGG in the sister chromatid since the surrounding DNA is both CGGCGGCGG..., leading to 3 extra copies of CGG in the final DNA sequence.
470:. While a mutation or epimutation in a DNA repair gene itself would not confer a selective advantage, such a repair defect may be carried along as a passenger in a cell when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. Such cells, with both proliferative advantages and one or more DNA repair defects (causing a very high mutation rate), likely give rise to the 20,000 to 80,000 total genome mutations frequently seen in cancers.
203:
catalyzed by RAG1 and RAG2 recombinases. Activation-Induced
Cytidine Deaminase (AID) then converts cytidine into uracil. Uracil normally does not exist in DNA, and thus the base is excised and the nick is converted into a double-stranded break which is repaired by non-homologous end joining (NHEJ). This procedure is very error-prone and leads to somatic hypermutation. This genomic instability is crucial in ensuring mammalian survival against infection.
2463:
167:
firing of late replication origins until the DNA breaks are fixed by phosphorylating CHK1 and CHK2, which results in a signaling cascade arresting the cell in S-phase. For single stranded breaks, replication occurs until the location of the break, then the other strand is nicked to form a double stranded break, which can then be repaired by Break
Induced Replication or homologous recombination using the sister
2475:
172:
caused by radiation. The yeast cells with defective rad9 failed to arrest following irradiation, continued cell division, and died rapidly; the cells with wild-type rad9 successfully arrested in late S/G2 phase and remained viable. The cells that arrested were able to survive due to the increased time in S/G2 phase allowing for DNA repair enzymes to function fully.
568:, an oncogene encoding a transcription factor, is translocated to a position after the promoter of the immunoglobulin gene, leading to dysregulation of c-myc transcription. Since immunoglobulins are essential to a lymphocyte and highly expressed to increase detection of antigens, c-myc is then also highly expressed, leading to transcription of its
372:, constitutes only 1.5% of the total genome. As pointed out above, ordinarily there are only an average of 0.35 mutations in the exome per generation (parent to child) in humans. In the entire genome (including non-protein coding regions) there are only about 70 new mutations per generation in humans.
349:). 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.
1933:
Berger MF; Hodis E; Heffernan TP; Deribe YL; Lawrence MS; Protopopov A; Ivanova E; Watson IR; Nickerson E; Ghosh P; Zhang H; Zeid R; Ren X; Cibulskis K; Sivachenko AY; Wagle N; Sucker A; Sougnez C; Onofrio R; Ambrogio L; Auclair D; Fennell T; Carter SL; Drier Y; Stojanov P; Singer MA; Voet D; Jing R;
584:
results from the translocation of the immunoglobulin promoter to the Bcl-2 gene, giving rise to high levels of Bcl-2 protein, which inhibits apoptosis. DNA-damaged B-cells no longer undergo apoptosis, leading to further mutations which could affect driver genes, leading to tumorigenesis. The location
324:
It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors. An average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may
193:
In both E. coli and
Saccharomyces pombe, transcription sites tend to have higher recombination and mutation rates. The coding or non-transcribed strand accumulates more mutations than the template strand. This is due to the fact that the coding strand is single-stranded during transcription, which is
478:
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,
279:
and
Alzheimer's 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,
180:
There are hotspots in the genome where DNA sequences are prone to gaps and breaks after inhibition of DNA synthesis such as in the aforementioned checkpoint arrest. These sites are called fragile sites, and can occur commonly as naturally present in most mammalian genomes or occur rarely as a result
157:
must perform its function well to result in a perfect copy of DNA. Mutations of proteins such as DNA polymerase or DNA ligase can lead to impairment of replication and lead to spontaneous chromosomal exchanges. Proteins such as Tel1 and Mec1 (ATR, ATM in humans) can detect single and double-stranded
563:
Cancers usually result from disruption of a tumor repressor or dysregulation of an oncogene. Knowing that B-cells experience DNA breaks during development can give insight to the genome of lymphomas. Many types of lymphoma are caused by chromosomal translocation, which can arise from breaks in DNA,
202:
In some portions of the genome, variability is essential to survival. One such locale is the Ig genes. In a pre-B cell, the region consists of all V, D, and J segments. During development of the B cell, a specific V, D, and J segment is chosen to be spliced together to form the final gene, which is
171:
as an error-free template. In addition to S-phase checkpoints, G1 and G2 checkpoints exist to check for transient DNA damage which could be caused by mutagens such as UV damage. An example is the
Saccharomyces pombe gene rad9 which arrests the cells in late S/G2 phase in the presence of DNA damage
542:
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 found to occur simultaneously in the majority of the 49 colon cancers evaluated. Some of these DNA repair deficiencies can be caused by
166:
result in a significant increase of chromosomal recombination. ATR responds specifically to stalled replication forks and single-stranded breaks resulting from UV damage while ATM responds directly to double-stranded breaks. These proteins also prevent progression into mitosis by inhibiting the
486:
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 expression was deficient because its pairing partner MLH1 was repressed due to
316:
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
2279:
Valeri, N; Gasparini, P; Fabbri, M; Braconi, C; Veronese, A; Lovat, F; Adair, B; Vannini, I; Fanini, F; Bottoni, A; Costinean, S; Sandhu, SK; Nuovo, GJ; Alder, H; Gafa, R; Calore, F; Ferracin, M; Lanza, G; Volinia, S; Negrini, M; Mcllhatton, MA; Amadori, D; Fishel, R; Croce, CM (2010).
106:), although some species present a very high karyotypic variability. In humans, mutations that would change an amino acid within the protein coding region of the genome occur at an average of only 0.35 per generation (less than one mutated protein per generation).
443:
The high frequency of mutations in the total genome within cancers suggests that, often, an early carcinogenic alteration may be a deficiency in DNA repair. Mutation rates substantially increase (sometimes by 100-fold) in cells defective in
1934:
Saksena G; Barretina J; Ramos AH; Pugh TJ; Stransky N; Parkin M; Winckler W; Mahan S; Ardlie K; Baldwin J; Wargo J; Schadendorf D; Meyerson M; Gabriel SB; Golub TR; Wagner SN; Lander ES; Getz G; Chin L; Garraway LA (May 2012).
487:
promoter methylation (PMS2 protein is unstable in the absence of MLH1). The other 10 cases of loss of PMS2 expression were likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
152:
must be able to navigate obstacles such as tightly wound chromatin with bound proteins, single and double stranded breaks which can lead to the stalling of the replication fork. Each protein or enzyme in the
65:
The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damage can cause inaccurate
215:
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. Five of them (
802:
Aguilera, A; Klein, H. L. (Aug 1998). "Genetic control of intrachromosomal recombination in
Saccharomyces cerevisiae. I. Isolation and genetic characterization of hyper-recombination mutations".
259:) seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this causes. Four of them (Huntington's disease, various
2238:
Truninger, K; Menigatti, M; Luz, J; Russell, A; Haider, R; Gebbers, JO; Bannwart, F; Yurtsever, H; Neuweiler, J; Riehle, HM; Cattaruzza, MS; Heinimann, K; Schär, P; Jiricny, J; Marra, G (2005).
431:
of DNA. The average number of DNA sequence mutations in the entire genome of a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (where melanomas have a higher
483:(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.
1723:
Cuozzo, C; Porcellini, A; Angrisano, T; Morano, A; Lee, B; Di Pardo, A; Messina, S; Iuliano, R; Fusco, A; Santillo, MR; Muller, MT; Chiariotti, L; Gottesman, ME; Avvedimento, EV (2007).
427:
As noted above, about 3 or 4 driver mutations and 60 passenger mutations occur in the exome (protein coding region) of a cancer. However, a much larger number of mutations occur in the
1496:
Hui, T.; Zhen, G.; HuiZhong, L.; BaoFu, Z.; Gang, W.; Qing, Z.; DongSheng, P.; JunNian, Z. (2015), "DNA damage response – A double-edged sword in cancer prevention and cancer therapy",
109:
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 (e.g.,
498:), 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
207:
can ensure millions of unique B-cell receptors; however, random repair by NHEJ introduces variation which can create a receptor that can bind with higher affinity to antigens.
86:
is very frequent, occurring on average more than 60,000 times a day in the genomes of human cells, any reduced DNA repair is likely an important source of genome instability.
2339:
Facista, A; Nguyen, H; Lewis, C; Prasad, AR; Ramsey, L; Zaitlin, B; Nfonsam, V; Krouse, RS; Bernstein, H; Payne, CM; Stern, S; Oatman, N; Banerjee, B; Bernstein, C (2012).
50:. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some
1095:"Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair"
1688:
Cunningham, FH; Fiebelkorn, S; Johnson, M; Meredith, C (2011). "A novel application of the Margin of
Exposure approach: segregation of tobacco smoke toxicants".
589:, suggesting that the oncogene was a potential target of AID, leading to a double-stranded break that was translocated to the immunoglobulin gene locus through
329:
rate will have as a consequence an increase in the acquisition of new mutations, increasing then the probability to develop a tumor. During the process of
2191:"O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions"
103:
479:
while the majority of these cancers had reduced MGMT expression due to methylation of the MGMT promoter region. Five reports, listed in the article
380:
The likely major underlying cause of mutations in cancer is DNA damage. For example, in the case of lung cancer, DNA damage is caused by agents in
292:, genome instability can occur prior to or as a consequence of transformation. Genome instability can refer to the accumulation of extra copies of
2431:
Ramiro, Almudena; San-Marin, Bernardo Reina; McBride, Kevin; Jankovic, Mila; Barreto, Vasco; Nussenzweig, Andre; Nussenzweig, Michel C. (2007).
117:) that modify the standard chromosomal complement. In these cases, it is indicated that the affected organism presents genome instability (also
823:"Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations"
1825:
Gottschalk, AJ; Timinszky, G; Kong, SE; Jin, J; Cai, Y; Swanson, SK; Washburn, MP; Florens, L; Ladurner, AG; Conaway, JW; Conaway, RC (2009).
1370:; Sengupta, A.; Jallepalli, P.V.; Shih, I.M.; Vogelstein, B.; Lengauer, C. (2002), "The role of chromosomal instability in tumor initiation",
1005:"A persistent RNA-DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro"
495:
1884:
Yost SE; Smith EN; Schwab RB; Bao L; Jung H; Wang X; Voest E; Pierce JP; Messer K; Parker BA; Harismendy O; Frazer KA (August 2012).
466:
past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to
1776:"Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island"
1530:
Lander ES; Linton LM; Birren B; Nusbaum C; Zody MC; Baldwin J; Devon K; Dewar K; Doyle M; FitzHugh W; et al. (February 2001).
515:
1460:
Cahill, D. P.; Kinzler, K. W.; Vogelstein, B.; Lengauer, C. (1999), "Genetic instability and darwinian selection in tumours",
2440:
586:
271:
types 1 and 2) often have an unusual expansion of repeat sequences in DNA, likely attributable to genome instability. Four (
129:, in which the cells present a chromosomic number that is either higher or lower than the normal complement for the species.
2052:"Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6"
872:"Double-strand breaks arising from replication through a nick are repaired by cohesin-dependent sister-chromatid exchange"
360:
pathways contributing to genomic instability, which promotes tumor survival, proliferation, and malignant transformation.
415:
alterations during DNA repair. Both mutations and epigenetic alterations (epimutations) can contribute to progression to
1886:"Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens"
317:
considered a "hallmark" for these cells. The unpredictable nature of these events are also a main contributor to the
400:
396:
83:
1054:"RNA Polymerase Modulators and DNA Repair Activities Resolve Conflicts between DNA Replication and Transcription"
539:
256:
55:
399:
is also very frequent, occurring on average more than 60,000 times a day in the genomes of human cells (see
602:
1093:
Schrader, Carol E.; Guikema, Jeroen E. J.; Linehan, Erin K.; Selsing, Erik; Stavnezer, Janet (Nov 2007).
2101:"Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation"
1993:"Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2"
1531:
1424:
Kinzler, K. W.; Vogelstein, B. (April 1997), "Cancer-susceptibility genes. Gatekeepers and caretakers",
2453:
590:
408:
276:
1226:
Corcos, D. (2012), "Unbalanced replication as a major source of genetic instability in cancer cells",
162:
to stabilize the replication fork in order to prevent its collapse. Mutations in Tel1, Mec1, and Rmr3
301:
110:
43:
1827:"Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler"
1262:
Storchova, Z.; Pellman, D. (2004), "From polyploidy to aneuploidy, genome instability and cancer",
455:. Also, chromosomal rearrangements and aneuploidy increase in humans defective in DNA repair gene
449:
94:
Usually, all cells in an individual in a given species (plant or animal) show a constant number of
580:
to the immunoglobulin locus. Cyclin D1 inhibits Rb, a tumor suppressor, leading to tumorigenesis.
240:
1052:
Trautinger, Brigitte W.; Jaktaji, Razieh P.; Rusakova, Ekaterina; Lloyd, Robert G. (July 2005).
552:
726:
Møller, P (2005). "Genotoxicity of environmental agents assessed by the alkaline comet assay".
456:
353:
264:
260:
248:
244:
236:
220:
280:
or a DNA repair pathway that normally repairs damage caused by oxidative stress is deficient.
2150:"Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients"
404:
403:). Externally and endogenously caused damages may be converted into mutations by inaccurate
305:
272:
216:
39:
2495:
2293:
2004:
1947:
1838:
1595:
1546:
1379:
1322:
1134:
Subba Rao, K (2007). "Mechanisms of disease: DNA repair defects and neurological disease".
981:
682:
573:
318:
2341:"Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer"
2240:"Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer"
8:
581:
445:
313:
309:
224:
204:
114:
2297:
2008:
1951:
1842:
1599:
1550:
1383:
1326:
686:
2367:
2340:
2316:
2281:
2215:
2190:
2166:
2149:
2125:
2100:
2076:
2051:
1968:
1935:
1910:
1885:
1861:
1826:
1802:
1775:
1751:
1724:
1665:
1640:
1616:
1583:
1343:
1310:
1309:
Vogelstein B; Papadopoulos N; Velculescu VE; Zhou S; Diaz LA; Kinzler KW (March 2013).
1287:
1240:
1203:
1178:
1159:
1029:
1004:
945:
920:
896:
871:
847:
822:
779:
754:
703:
670:
646:
621:
585:
of translocation in the oncogene shares structural properties of the target regions of
491:
462:
A deficiency in DNA repair itself can allow DNA damages to accumulate, and error-prone
268:
252:
228:
182:
138:
59:
1474:
1402:
416:
2505:
2436:
2413:
2372:
2321:
2261:
2220:
2171:
2130:
2081:
2032:
2027:
1992:
1973:
1915:
1866:
1807:
1756:
1705:
1670:
1621:
1564:
1513:
1479:
1443:
1407:
1348:
1279:
1245:
1208:
1151:
1116:
1075:
1034:
985:
950:
901:
852:
784:
735:
708:
694:
651:
569:
232:
51:
1291:
1194:
1163:
2403:
2362:
2352:
2311:
2301:
2251:
2210:
2202:
2161:
2120:
2112:
2071:
2063:
2050:
Hegan DC; Narayanan L; Jirik FR; Edelmann W; Liskay RM; Glazer PM (December 2006).
2022:
2012:
1963:
1955:
1905:
1897:
1856:
1846:
1797:
1787:
1746:
1736:
1697:
1660:
1652:
1611:
1603:
1554:
1505:
1469:
1433:
1397:
1387:
1367:
1338:
1330:
1271:
1235:
1198:
1190:
1143:
1106:
1065:
1024:
1016:
977:
940:
932:
891:
883:
842:
834:
774:
766:
698:
690:
641:
633:
2116:
2500:
2479:
2256:
2239:
1792:
1741:
1509:
1070:
1053:
345:
1584:"Analysis of genetic inheritance in a family quartet by whole-genome sequencing"
1111:
1094:
936:
770:
435:
mutation frequency) the total number of DNA sequence mutations is about 80,000.
337:
cells acquire mutations in genes responsible for maintaining genome integrity (
2467:
1641:"Estimating the human mutation rate using autozygosity in a founder population"
339:
1701:
343:), as well as in genes that are directly controlling cellular proliferation (
2489:
1308:
968:
Durkin, Sandra G.; Glover, Thomas W. (Dec 2007). "Chromosome
Fragile Sites".
887:
428:
392:
330:
2306:
2206:
2067:
1851:
1607:
1334:
2417:
2376:
2325:
2265:
2224:
2134:
2085:
2017:
1977:
1919:
1870:
1811:
1760:
1709:
1674:
1625:
1568:
1517:
1483:
1411:
1392:
1352:
1283:
1249:
1212:
1155:
1120:
1079:
1038:
989:
905:
856:
788:
739:
712:
655:
384:
35:
2357:
2175:
2036:
1447:
954:
637:
148:
In the cell cycle, DNA is usually most vulnerable during replication. The
2408:
2391:
1901:
1147:
1020:
921:"Cell cycle arrest of cdc mutants and specificity of the RAD9 checkpoint"
480:
467:
412:
325:
be "passenger" mutations Any genetic or epigenetic lesion increasing the
75:
67:
2099:
Tutt AN; van Oostrom CT; Ross GM; van Steeg H; Ashworth A (March 2002).
1959:
368:
The protein coding regions of the human genome, collectively called the
2098:
1991:
Narayanan L; Fritzell JA; Baker SM; Liskay RM; Glazer PM (April 1997).
1990:
838:
503:
463:
452:
357:
297:
126:
95:
47:
2049:
1932:
1559:
1438:
577:
235:) have a defect in the DNA nucleotide excision repair pathway. Six (
168:
154:
149:
99:
1656:
1275:
2462:
1687:
1529:
558:
548:
544:
388:
326:
163:
159:
125:). The process of genome instability often leads to a situation of
79:
71:
31:
16:
High frequency of mutations within the genome of a cellular lineage
2189:
Halford S; Rowan A; Sawyer E; Talbot I; Tomlinson I (June 2005).
438:
381:
334:
2392:"Oncogenic chromosomal translocations and human cancer (Review)"
2282:"Modulation of mismatch repair and genomic stability by miR-155"
2188:
1722:
1459:
1365:
289:
2430:
1051:
70:
DNA synthesis past the damage or errors in repair, leading to
1936:"Melanoma genome sequencing reveals frequent PREX2 mutations"
1883:
1639:
Campbell CD; Chong JX; Malig M; et al. (November 2012).
1092:
565:
535:
531:
511:
507:
499:
432:
395:, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene).
369:
2278:
2237:
363:
1725:"DNA damage, homology-directed repair, and DNA methylation"
755:"Rates and fitness consequences of new mutations in humans"
527:
523:
519:
1824:
1638:
1773:
293:
2338:
1582:
Roach JC; Glusman G; Smit AF; et al. (April 2010).
1581:
210:
1003:
Grabczyk, E.; Mancuso, M.; Sammarco, M. C. (Aug 2007).
1002:
188:
869:
82:
reductions in expression of DNA repair genes. Because
2451:
1532:"Initial sequencing and analysis of the human genome"
1176:
870:
Cortes-Ledesma, Felipe; Aguilera, Andres (Sep 2006).
564:
leading to incorrect joining. In Burkitt's lymphoma,
1495:
422:
411:). In addition, DNA damages can also give rise to
668:
473:
104:List of number of chromosomes of various organisms
1423:
671:"Implications of genetic heterogeneity in cancer"
2487:
1261:
559:Lymphomas as a consequence of genome instability
918:
496:Frequencies of epimutations in DNA repair genes
375:
197:
132:
1774:O'Hagan, HM; Mohammad, HP; Baylin, SB (2008).
439:Cause of high frequency of mutations in cancer
74:. Another source of genome instability may be
1304:
1302:
1300:
1177:Jeppesen, DK; Bohr, VA; Stevnsner, T (2011).
801:
2182:
1926:
1877:
1523:
1179:"DNA repair deficiency in neurodegeneration"
967:
919:Weinert, T. A.; Hartwell, L. H. (May 1993).
752:
572:, which are involved in cell proliferation.
397:Endogenous (metabolically-caused) DNA damage
84:endogenous (metabolically-caused) DNA damage
669:Schmitt, MW; Prindle, MJ; Loeb, LA (2012).
619:
1297:
603:Hallmarks of aging > Genome instability
143:
2407:
2366:
2356:
2315:
2305:
2255:
2214:
2165:
2124:
2075:
2026:
2016:
1984:
1967:
1909:
1860:
1850:
1801:
1791:
1750:
1740:
1664:
1615:
1558:
1473:
1437:
1401:
1391:
1342:
1239:
1202:
1133:
1110:
1069:
1028:
944:
895:
846:
778:
702:
645:
364:Low frequency of mutations without cancer
89:
38:. These mutations can include changes in
158:breaks and recruit factors such as Rmr3
98:, which constitute what is known as the
275:, ataxia-telangiectasia-like disorder,
2488:
2147:
1225:
982:10.1146/annurev.genet.41.042007.165900
725:
662:
468:epigenetic alterations or epimutations
2389:
2043:
613:
211:In neuronal and neuromuscular disease
2092:
820:
189:Transcription-associated instability
13:
1228:American Journal of Blood Research
407:or inaccurate DNA repair (e.g. by
14:
2517:
423:Very frequent mutations in cancer
2473:
2461:
695:10.1111/j.1749-6632.2012.06590.x
401:DNA damage (naturally occurring)
175:
102:defining this species (see also
30:) refers to a high frequency of
2424:
2383:
2332:
2272:
2231:
2141:
1818:
1767:
1716:
1681:
1632:
1575:
1489:
1453:
1417:
1359:
1255:
1219:
1195:10.1016/j.pneurobio.2011.04.013
1170:
1127:
1086:
1045:
996:
474:DNA repair deficiency in cancer
312:, single-strand breaks in DNA,
961:
912:
863:
814:
795:
753:Keightley PD (February 2012).
746:
719:
622:"Bacterial Genome Instability"
620:Darmon, E; Leach, DRF (2014).
576:is characterized by fusion of
1:
2435:. Elsevier. pp. 75–107.
1475:10.1016/S0168-9525(99)01874-0
607:
321:observed among tumour cells.
257:amyotrophic lateral sclerosis
58:or the neuromuscular disease
56:amyotrophic lateral sclerosis
2257:10.1053/j.gastro.2005.01.056
1997:Proc. Natl. Acad. Sci. U.S.A
1793:10.1371/journal.pgen.1000155
1742:10.1371/journal.pgen.0030110
1510:10.1016/j.canlet.2014.12.038
1071:10.1016/j.molcel.2005.06.004
728:Basic Clin Pharmacol Toxicol
553:miRNA, DNA repair and cancer
376:Cause of mutations in cancer
356:has an inhibitory effect on
283:
198:Increase Genetic Variability
133:Causes of genome instability
7:
2117:10.1093/embo-reports/kvf037
1112:10.4049/jimmunol.179.9.6064
771:10.1534/genetics.111.134668
596:
10:
2522:
1372:Proc. Natl. Acad. Sci. USA
1311:"Cancer genome landscapes"
600:
450:homologous recombinational
429:non-protein-coding regions
409:non-homologous end joining
302:chromosomal translocations
277:Nijmegen breakage syndrome
239:with axonal neuropathy-1,
136:
111:chromosomal translocations
44:chromosomal rearrangements
1702:10.1016/j.fct.2011.07.019
970:Annual Review of Genetics
937:10.1093/genetics/134.1.63
626:Microbiol. Mol. Biol. Rev
1831:Proc Natl Acad Sci U S A
888:10.1038/sj.embor.7400774
821:Cobb, J. A. (Dec 2005).
2390:Zheng, Jie (Nov 2013).
2307:10.1073/pnas.1002472107
2207:10.1136/gut.2004.059535
1852:10.1073/pnas.0906920106
1608:10.1126/science.1186802
1335:10.1126/science.1235122
827:Genes & Development
551:article section titled
261:spinocerebellar ataxias
144:DNA Replication Defects
123:chromosomic instability
34:within the genome of a
2433:Advances in Immunology
2286:Proc Natl Acad Sci USA
2148:German, J (Mar 1969).
2018:10.1073/pnas.94.7.3122
1393:10.1073/pnas.202617399
1009:Nucleic Acids Research
354:tumor microenvironment
306:chromosomal inversions
237:spinocerebellar ataxia
90:Usual genome situation
40:nucleic acid sequences
2358:10.1186/2041-9414-3-3
2068:10.1093/carcin/bgl079
1264:Nat Rev Mol Cell Biol
1136:Nat Clin Pract Neurol
1099:Journal of Immunology
638:10.1128/MMBR.00035-13
547:as summarized in the
464:translesion synthesis
405:translesion synthesis
273:ataxia-telangiectasia
217:xeroderma pigmentosum
205:V, D, J recombination
2409:10.3892/or.2013.2677
1148:10.1038/ncpneuro0448
574:Mantle cell lymphoma
387:tobacco smoke (e.g.
314:double-strand breaks
241:Huntington's disease
2298:2010PNAS..107.6982V
2009:1997PNAS...94.3122N
1960:10.1038/nature11071
1952:2012Natur.485..502B
1843:2009PNAS..10613770G
1600:2010Sci...328..636R
1551:2001Natur.409..860L
1384:2002PNAS...9916226N
1327:2013Sci...339.1546V
687:2012NYASA1267..110S
582:Follicular lymphoma
446:DNA mismatch repair
333:, it is known that
265:Friedreich's ataxia
249:Parkinson's disease
245:Alzheimer's disease
225:trichothiodystrophy
221:Cockayne's syndrome
119:genetic instability
28:genomic instability
24:genetic instability
1902:10.1093/nar/gks299
1021:10.1093/nar/gkm589
839:10.1101/gad.361805
492:cancer epigenetics
269:myotonic dystrophy
183:replication stress
139:Replication stress
60:myotonic dystrophy
20:Genome instability
2442:978-0-12-373706-9
2292:(15): 6982–6987.
1890:Nucleic Acids Res
1696:(11): 2921–2933.
1690:Food Chem Toxicol
1545:(6822): 860–921.
1462:Trends Cell Biol.
1321:(6127): 1546–58.
1015:(16): 5351–5359.
833:(24): 3055–3069.
734:(Suppl 1): 1–42.
233:triple-A syndrome
54:diseases such as
52:neurodegenerative
2513:
2478:
2477:
2476:
2466:
2465:
2457:
2447:
2446:
2428:
2422:
2421:
2411:
2402:(5): 2011–2019.
2396:Oncology Reports
2387:
2381:
2380:
2370:
2360:
2336:
2330:
2329:
2319:
2309:
2276:
2270:
2269:
2259:
2250:(5): 1160–1171.
2244:Gastroenterology
2235:
2229:
2228:
2218:
2186:
2180:
2179:
2169:
2145:
2139:
2138:
2128:
2096:
2090:
2089:
2079:
2047:
2041:
2040:
2030:
2020:
1988:
1982:
1981:
1971:
1930:
1924:
1923:
1913:
1881:
1875:
1874:
1864:
1854:
1822:
1816:
1815:
1805:
1795:
1771:
1765:
1764:
1754:
1744:
1720:
1714:
1713:
1685:
1679:
1678:
1668:
1636:
1630:
1629:
1619:
1579:
1573:
1572:
1562:
1560:10.1038/35057062
1536:
1527:
1521:
1520:
1493:
1487:
1486:
1477:
1457:
1451:
1450:
1441:
1439:10.1038/386761a0
1421:
1415:
1414:
1405:
1395:
1378:(25): 16226–31,
1363:
1357:
1356:
1346:
1306:
1295:
1294:
1259:
1253:
1252:
1243:
1223:
1217:
1216:
1206:
1174:
1168:
1167:
1131:
1125:
1124:
1114:
1105:(9): 6064–6071.
1090:
1084:
1083:
1073:
1049:
1043:
1042:
1032:
1000:
994:
993:
965:
959:
958:
948:
916:
910:
909:
899:
867:
861:
860:
850:
818:
812:
811:
799:
793:
792:
782:
750:
744:
743:
723:
717:
716:
706:
675:Ann N Y Acad Sci
666:
660:
659:
649:
617:
543:epimutations in
391:, formaldehyde,
346:gatekeeper genes
36:cellular lineage
2521:
2520:
2516:
2515:
2514:
2512:
2511:
2510:
2486:
2485:
2484:
2474:
2472:
2460:
2452:
2450:
2443:
2429:
2425:
2388:
2384:
2337:
2333:
2277:
2273:
2236:
2232:
2187:
2183:
2146:
2142:
2097:
2093:
2048:
2044:
1989:
1985:
1946:(7399): 502–6.
1931:
1927:
1882:
1878:
1837:(33): 13770–4.
1823:
1819:
1786:(8): e1000155.
1772:
1768:
1721:
1717:
1686:
1682:
1657:10.1038/ng.2418
1651:(11): 1277–81.
1637:
1633:
1594:(5978): 636–9.
1580:
1576:
1534:
1528:
1524:
1494:
1490:
1468:(12): M57–M60,
1458:
1454:
1432:(6627): 761–3,
1422:
1418:
1368:Komarova, N. L.
1364:
1360:
1307:
1298:
1276:10.1038/nrm1276
1260:
1256:
1224:
1220:
1175:
1171:
1132:
1128:
1091:
1087:
1050:
1046:
1001:
997:
966:
962:
917:
913:
868:
864:
819:
815:
800:
796:
751:
747:
724:
720:
667:
663:
618:
614:
610:
605:
599:
561:
476:
441:
425:
378:
366:
340:caretaker genes
286:
253:Down's syndrome
229:Down's syndrome
213:
200:
191:
178:
146:
141:
135:
92:
17:
12:
11:
5:
2519:
2509:
2508:
2503:
2498:
2483:
2482:
2470:
2449:
2448:
2441:
2423:
2382:
2331:
2271:
2230:
2201:(6): 797–802.
2181:
2160:(2): 196–227.
2154:Am J Hum Genet
2140:
2091:
2062:(12): 2402–8.
2056:Carcinogenesis
2042:
1983:
1925:
1876:
1817:
1766:
1715:
1680:
1631:
1574:
1522:
1498:Cancer Letters
1488:
1452:
1416:
1366:Nowak, M. A.;
1358:
1296:
1254:
1218:
1189:(2): 166–200.
1183:Prog Neurobiol
1169:
1126:
1085:
1064:(2): 247–258.
1058:Molecular Cell
1044:
995:
976:(1): 169–192.
960:
911:
882:(9): 919–926.
862:
813:
794:
765:(2): 295–304.
745:
718:
681:(1): 110–116.
661:
611:
609:
606:
598:
595:
560:
557:
475:
472:
440:
437:
424:
421:
377:
374:
365:
362:
285:
282:
212:
209:
199:
196:
190:
187:
177:
174:
145:
142:
137:Main article:
134:
131:
91:
88:
15:
9:
6:
4:
3:
2:
2518:
2507:
2504:
2502:
2499:
2497:
2494:
2493:
2491:
2481:
2471:
2469:
2464:
2459:
2458:
2455:
2444:
2438:
2434:
2427:
2419:
2415:
2410:
2405:
2401:
2397:
2393:
2386:
2378:
2374:
2369:
2364:
2359:
2354:
2350:
2346:
2345:Genome Integr
2342:
2335:
2327:
2323:
2318:
2313:
2308:
2303:
2299:
2295:
2291:
2287:
2283:
2275:
2267:
2263:
2258:
2253:
2249:
2245:
2241:
2234:
2226:
2222:
2217:
2212:
2208:
2204:
2200:
2196:
2192:
2185:
2177:
2173:
2168:
2163:
2159:
2155:
2151:
2144:
2136:
2132:
2127:
2122:
2118:
2114:
2111:(3): 255–60.
2110:
2106:
2102:
2095:
2087:
2083:
2078:
2073:
2069:
2065:
2061:
2057:
2053:
2046:
2038:
2034:
2029:
2024:
2019:
2014:
2010:
2006:
2003:(7): 3122–7.
2002:
1998:
1994:
1987:
1979:
1975:
1970:
1965:
1961:
1957:
1953:
1949:
1945:
1941:
1937:
1929:
1921:
1917:
1912:
1907:
1903:
1899:
1895:
1891:
1887:
1880:
1872:
1868:
1863:
1858:
1853:
1848:
1844:
1840:
1836:
1832:
1828:
1821:
1813:
1809:
1804:
1799:
1794:
1789:
1785:
1781:
1777:
1770:
1762:
1758:
1753:
1748:
1743:
1738:
1734:
1730:
1726:
1719:
1711:
1707:
1703:
1699:
1695:
1691:
1684:
1676:
1672:
1667:
1662:
1658:
1654:
1650:
1646:
1642:
1635:
1627:
1623:
1618:
1613:
1609:
1605:
1601:
1597:
1593:
1589:
1585:
1578:
1570:
1566:
1561:
1556:
1552:
1548:
1544:
1540:
1533:
1526:
1519:
1515:
1511:
1507:
1503:
1499:
1492:
1485:
1481:
1476:
1471:
1467:
1463:
1456:
1449:
1445:
1440:
1435:
1431:
1427:
1420:
1413:
1409:
1404:
1399:
1394:
1389:
1385:
1381:
1377:
1373:
1369:
1362:
1354:
1350:
1345:
1340:
1336:
1332:
1328:
1324:
1320:
1316:
1312:
1305:
1303:
1301:
1293:
1289:
1285:
1281:
1277:
1273:
1269:
1265:
1258:
1251:
1247:
1242:
1237:
1233:
1229:
1222:
1214:
1210:
1205:
1200:
1196:
1192:
1188:
1184:
1180:
1173:
1165:
1161:
1157:
1153:
1149:
1145:
1142:(3): 162–72.
1141:
1137:
1130:
1122:
1118:
1113:
1108:
1104:
1100:
1096:
1089:
1081:
1077:
1072:
1067:
1063:
1059:
1055:
1048:
1040:
1036:
1031:
1026:
1022:
1018:
1014:
1010:
1006:
999:
991:
987:
983:
979:
975:
971:
964:
956:
952:
947:
942:
938:
934:
930:
926:
922:
915:
907:
903:
898:
893:
889:
885:
881:
877:
873:
866:
858:
854:
849:
844:
840:
836:
832:
828:
824:
817:
810:(4): 779–790.
809:
805:
798:
790:
786:
781:
776:
772:
768:
764:
760:
756:
749:
741:
737:
733:
729:
722:
714:
710:
705:
700:
696:
692:
688:
684:
680:
676:
672:
665:
657:
653:
648:
643:
639:
635:
631:
627:
623:
616:
612:
604:
594:
592:
588:
583:
579:
575:
571:
567:
556:
554:
550:
546:
541:
537:
533:
529:
525:
521:
517:
513:
509:
505:
501:
497:
494:(see section
493:
488:
484:
482:
471:
469:
465:
460:
458:
454:
451:
447:
436:
434:
430:
420:
418:
414:
410:
406:
402:
398:
394:
393:acrylonitrile
390:
386:
383:
373:
371:
361:
359:
355:
350:
348:
347:
342:
341:
336:
332:
331:tumorogenesis
328:
322:
320:
319:heterogeneity
315:
311:
308:, chromosome
307:
303:
299:
295:
291:
281:
278:
274:
270:
266:
262:
258:
254:
250:
246:
242:
238:
234:
230:
226:
222:
218:
208:
206:
195:
186:
184:
176:Fragile Sites
173:
170:
165:
161:
156:
151:
140:
130:
128:
124:
120:
116:
112:
107:
105:
101:
97:
87:
85:
81:
77:
73:
69:
63:
61:
57:
53:
49:
45:
41:
37:
33:
29:
25:
21:
2432:
2426:
2399:
2395:
2385:
2348:
2344:
2334:
2289:
2285:
2274:
2247:
2243:
2233:
2198:
2194:
2184:
2157:
2153:
2143:
2108:
2104:
2094:
2059:
2055:
2045:
2000:
1996:
1986:
1943:
1939:
1928:
1896:(14): e107.
1893:
1889:
1879:
1834:
1830:
1820:
1783:
1779:
1769:
1732:
1728:
1718:
1693:
1689:
1683:
1648:
1644:
1634:
1591:
1587:
1577:
1542:
1538:
1525:
1501:
1497:
1491:
1465:
1461:
1455:
1429:
1425:
1419:
1375:
1371:
1361:
1318:
1314:
1270:(1): 45–54,
1267:
1263:
1257:
1234:(3): 160–9,
1231:
1227:
1221:
1186:
1182:
1172:
1139:
1135:
1129:
1102:
1098:
1088:
1061:
1057:
1047:
1012:
1008:
998:
973:
969:
963:
931:(1): 63–80.
928:
924:
914:
879:
876:EMBO Reports
875:
865:
830:
826:
816:
807:
803:
797:
762:
758:
748:
731:
727:
721:
678:
674:
664:
629:
625:
615:
562:
489:
485:
477:
461:
442:
426:
379:
367:
351:
344:
338:
323:
287:
214:
201:
192:
179:
147:
122:
118:
108:
93:
64:
27:
23:
19:
18:
2496:Chromosomes
1735:(7): e110.
1504:(1): 8–16,
632:(1): 1–39.
481:Epigenetics
298:chromosomes
96:chromosomes
68:translesion
2490:Categories
1780:PLOS Genet
1729:PLOS Genet
1645:Nat. Genet
608:References
601:See also:
453:DNA repair
413:epigenetic
358:DNA repair
127:aneuploidy
121:, or even
80:mutational
76:epigenetic
48:aneuploidy
578:cyclin D1
545:microRNAs
385:genotoxic
382:exogenous
310:deletions
284:In cancer
169:chromatid
155:replisome
150:replisome
115:deletions
100:karyotype
32:mutations
2506:Mutation
2480:Medicine
2418:23970180
2377:22494821
2351:(1): 3.
2326:20351277
2266:15887099
2225:15888787
2135:11850397
2105:EMBO Rep
2086:16728433
1978:22622578
1920:22492626
1871:19666485
1812:18704159
1761:17616978
1710:21802474
1675:23001126
1626:20220176
1569:11237011
1518:25528631
1484:10611684
1412:12446840
1353:23539594
1292:11985415
1284:14708009
1250:23119227
1213:21550379
1164:12930631
1156:17342192
1121:17947680
1080:16039593
1039:17693431
990:17608616
925:Genetics
906:16888651
857:16357221
804:Genetics
789:22345605
759:Genetics
740:15859009
713:22954224
656:24600039
597:In aging
593:repair.
549:MicroRNA
389:acrolein
327:mutation
164:helicase
160:helicase
72:mutation
2468:Biology
2454:Portals
2368:3351028
2317:2872463
2294:Bibcode
2216:1774551
2176:5770175
2167:1706430
2126:1084010
2077:2612936
2037:9096356
2005:Bibcode
1969:3367798
1948:Bibcode
1911:3413110
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