DNA double-strand break repair and chromosome translocations

Agarwal, Sheba; Tafel, Agnieszka A.; Kanaar, Roland

doi:10.1016/j.dnarep.2006.05.029

Cited by 95 publications

(65 citation statements)

References 56 publications

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“…Induced DNA DSBs are potentially lethal to the cell and therefore must be rapidly recognized and repaired to avoid genetic damage (Agarwal et al, 2006). Not unexpectedly there are cellular mechanisms in place to recognize and signal the presence of DNA DSB to the cell-cycle checkpoints to delay the passage of cells through the cycle and facilitate DNA repair (Zhou and Elledge, 2000).…”

Section: Introductionmentioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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Section: Introductionmentioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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“…However, it has also been recognized that HR also has the potential to induce genome instability, acting inappropriately or in an unregulated fashion (Elliott and Jasin 2002;Kolodner et al 2002). For example, ectopic recombination between repeated DNA is a potent driver of chromosomal rearrangements, as suspected from genomic analysis and established in genetic model systems (Szankasi et al 1986;Cooper et al 1997;Agarwal et al 2006;Haber 2006;Weinstock et al 2006;Putnam et al 2009;Song et al 2014). Furthermore, the identification of synthetic lethality in double mutants that depend on HR, called recombination-dependent lethality, shows that uncontrolled HR leads to potentially toxic intermediates and cell death (Heude et al 1995;Schild 1995;Gangloff et al 2000;Fabre et al 2002;Bastin-Shanower et al 2003).…”

Section: Quality Control By Pathway Reversibilitymentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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“…Translocations and other gross chromosomal rearrangements (GCRs), i.e., deletions and inversions, are often observed in cancer cells (6). Recently, seven pathways that suppress (7)(8)(9) and four pathways that are required for the formation of GCRs (10)(11)(12) have been identified in yeast. From the great number and redundancy of factors involved in GCR suppression, it can be concluded that any genomic rearrangement is highly deleterious to cells, and, once escaped from control, it can have a massive impact on cellular morphology and physiology.…”

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confidence: 99%

Cellular and molecular effects of nonreciprocal chromosome translocations in Saccharomyces cerevisiae

Nikitin

Tosato²,

Zavec³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Saccharomyces cerevisiae strains harboring a nonreciprocal, bridgeinduced translocation (BIT) between chromosomes VIII and XV exhibited an abnormal phenotype comprising elongated buds and multibudded, unevenly nucleated pseudohyphae. In these cells, we found evidence of molecular effects elicited by the translocation event and specific for its particular genomic location. Expression of genes flanking both translocation breakpoints increased up to five times, correlating with an increased RNA polymerase II binding to their promoters and with their histone acetylation pattern. Microarray data, CHEF, and quantitative PCR confirmed the data on the dosage of genes present on the chromosomal regions involved in the translocation, indicating that telomeric fragments were either duplicated or integrated mostly on chromosome XI. FACS analysis revealed that the majority of translocant cells were blocked in G1 phase and a few of them in G2. Some cells showed a posttranslational decrease of cyclin B1, in agreement with elongated buds diagnostic of a G2/M phase arrest. The actin1 protein was in some cases modified, possibly explaining the abnormal morphology of the cells. Together with the decrease in Rad53p and the lack of its phosphorylation, these results indicate that these cells have undergone adaptation after checkpointmediated G2/M arrest after chromosome translocation. These BIT translocants could serve as model systems to understand further the cellular and molecular effects of chromosome translocation and provide fundamental information on its etiology of neoplastic transformation in mammals.DNA integration ͉ yeast ͉ genome expression ͉ genome dynamics ͉ transcription

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DNA double-strand break repair and chromosome translocations

Cited by 95 publications

References 56 publications

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

Regulation of Recombination and Genomic Maintenance

Cellular and molecular effects of nonreciprocal chromosome translocations in Saccharomyces cerevisiae

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