Multiple Pathways Leading to Genomic Instabiligy and Tumorigenesis

Sweezy, Mark A.; Fishel, Richard

doi:10.1111/j.1749-6632.1994.tb52810.x

Cited by 16 publications

(10 citation statements)

References 47 publications

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“…The best known machinery involved in repairing potentially lethal DNA damage, especially double-strand breaks, is genetic recombination. 5 In fact the repair of DNA lesions may account for majority of the recombination occurring in mitosis. 6 Recombination plays an important role in maintaining the genetic integrity of a cell, including DNA repair 7 and proper segregation of chromosomes in meiosis.…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

Shammas

Reis

Koley

et al. 2009

Blood

127

173

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A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in cancer cells has important implications in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to an increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by small inhibitory RNA (siRNAs) targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the ge- IntroductionGenetic changes observed at the chromosomal level or at the nucleotide sequence level are associated with the development and progression of malignant phenotypes. Although some specific cancers are associated with and attributed to specific cytogenetic and molecular aberrations, for example, chronic myelogenous leukemia or acute promyelocytic leukemia, the majority of cancers display a complex spectra of diverse genetic alterations apparent at diagnosis and acquire additional changes with progression of the disease. 1 Because the large-scale chromosomal alterations that arise frequently in cancer cells occur infrequently in normal cells, [2][3][4] it implies that the control mechanisms that maintain the integrity of chromosomes in normal cells are disrupted in cancer cells.A variety of intrinsic or extrinsic chemical as well as physical factors damage DNA in living organisms which, if not repaired, can lead to mutations and cellular transformation. The best known machinery involved in repairing potentially lethal DNA damage, especially double-strand breaks, is genetic recombination. 5 In fact the repair of DNA lesions may account for majority of the recombination occurring in mitosis. 6 Recombination plays an important role in maintaining the genetic integrity of a cell, including DNA repair 7 and proper segregation of chromosomes in meiosis. 8 In the normal cellular environment, recombination-associated proteins are highly regulated, precise, and exhibit considerable specificity for DNA sequences, which have either an extensive homology or a characteristic signal sequence. However, with its significant ability to modify DNA, if dysregulated, it can lead to genomic instability. Recombination can be induced by several chemicals, radiation, and oncogenic viruses. [9][10][11][12][13][14] The induction or overexpression of a recombination pathway may result in DNA rearrangements, leading to oncogene activation 15 and/or the loss of hemizygous functional alleles of tumor suppressor genes.Aberrant or dysregulated recombination has been implicated in chromosome translocation, 9,16,17 gene amplification, 18 and telomere maintenance 19 and may therefore underlie the chromosomal aberrations observed with high frequency i...

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Section: Introductionmentioning

confidence: 99%

Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

Shammas

Reis

Koley

et al. 2009

Blood

127

173

View full text Add to dashboard Cite

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“…3 Colorectal cancer has been shown to arise through at least two distinct genetic pathways: one involving chromosomal instability, and the other involving microsatellite instability (MSI). [4][5][6] Tumors characterized by chromosomal instability demonstrate a high frequency of allelic loss. These allelic deletions are detected by loss of heterozygosity (LOH) analyses and have been reported in colorectal cancer on a large number of chromosomal arms (3p, 4p, 5q, 8p, 17p, and 18q).…”

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confidence: 99%

Association Between Recurrence of Sporadic Colorectal Cancer, High Level of Microsatellite Instability, and Loss of Heterozygosity at Chromosome 18q

Sarli

Bottarelli²,

Bader³

et al. 2004

Diseases of the Colon &Amp; Rectum

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“…For example, chromosomal fragments losing or gaining a centromere (acentric or dicentric chromosomes) tend to segregate abnormally. Genetic recombination reduces mutations arising from error-prone repair, and is essential for the repair of double-strand breaks (Resnick et aL, 1989;Sweezy and Fishel 1994); its occurrence in mitotic cells may thus be predominantly or entirely repair-related (Roca and Cox 1990). Surprisingly, the repair of DNA damage appears to utilize both homologous and nonhomologous recombination pathways (Sweezy and Fishel 1994), which are described in greater detail below.…”

Section: Relationship Of Homologous Recombination To Dna Repairmentioning

confidence: 97%

“…Genetic recombination reduces mutations arising from error-prone repair, and is essential for the repair of double-strand breaks (Resnick et aL, 1989;Sweezy and Fishel 1994); its occurrence in mitotic cells may thus be predominantly or entirely repair-related (Roca and Cox 1990). Surprisingly, the repair of DNA damage appears to utilize both homologous and nonhomologous recombination pathways (Sweezy and Fishel 1994), which are described in greater detail below. Moreover, the Rad52 protein, although intimately involved in homologous recombination through interaction with Rad51, is not required for intrachromosomal "gene conversion" or for repair of several types of DNA damage (Yamaguchi-lwai et aL 1998)…”

Section: Relationship Of Homologous Recombination To Dna Repairmentioning

confidence: 97%

“…Although its frequency per kilobase of target DNA is much lower than that for homologous recombination, the total over the whole genome can be substantial (Mansour etaL, 1988(Mansour etaL, , 1993. Thus, stable integration of transfected DNA occurs predominantly through illegitimate recombination (Waldman and Waldman 1990; Sweezy and Fishel 1994), even when homologous recombination is greatly enhanced by gene targeting with sequences identical to genomic DNA (Folger et aL 1985; Mansour et aL, 1988;Sedivy and Sharp 1989).…”

Section: Varieties Of Recombinationmentioning

confidence: 98%

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Recombination and its roles in DNA repair, cellular immortalization and cancer

Shammas

Reis

1999

AGE

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Genetic recombination is the creation of new gene combinations in a cell or gamete, which differ from those of progenitor cells or parental gametes. In eukaryotes, recombination may occur at mitosis or meiosis. Mitotic recombination plays an indispensable role in DNA repair, which presumably directed its early evolution; the multiplicity of recombination genes and pathways may be best understood in this context, although they have acquired important additional functions in generating diversity, both somatically (increasing the immune repertoire) and in germ line (facilitating evolution). Chromosomal homologous recombination and HsRad51 recombinase expression are increased in both immortal and preimmortal transformed cells, and may favor the occurrence of multiple oncogenic mutations. Tumorigenesis in vivo is frequently associated with karyotypic instability, locus-specific gene rearrangements, and loss of heterozygosity at tumor suppressor loci - all of which can be recombinationally mediated. Genetic defects which increase the rate of somatic mutation (several of which feature elevated recombination) are associated with early incidence and high risk for a variety of cancers. Moreover, carcinogenic agents appear to quite consistently stimulate homologous recombination. If cells with high recombination arise, either spontaneously or in response to "recombinogens," and predispose to the development of cancer, what selective advantage could favor these cells prior to the occurrence of growth-promoting mutations? We propose that the augmentation of telomere-telomere recombination may provide just such an advantage, to hyper-recombinant cells within a population of telomerase-negative cells nearing their replicative (Hayflick) limit, by extending telomeres in some progeny cells and thus allowing their continued proliferation.

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Multiple Pathways Leading to Genomic Instabiligy and Tumorigenesis

Cited by 16 publications

References 47 publications

Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

Dysfunctional homologous recombination mediates genomic instability and progression in myeloma

Association Between Recurrence of Sporadic Colorectal Cancer, High Level of Microsatellite Instability, and Loss of Heterozygosity at Chromosome 18q

Recombination and its roles in DNA repair, cellular immortalization and cancer

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