Chromosome Instability Syndromes: Lessons for Carcinogenesis

Meyn, M. Stephen

doi:10.1007/978-3-642-60505-5_6

Cited by 50 publications

(55 citation statements)

References 352 publications

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“…Spontaneous hyper-recombination may be such a mechanism, as it is also a defining feature of the human cancer predisposition syndromes ataxia telangiectasia, Bloom's syndrome, and Fanconi's anemia with similar chromosomal abnormalities (see Introduction; ref. 6), although the underlying mechanisms may be different. The phenotype of BRCA1/2-deficient cells seems similar to that of FANC-and ATM-deficient cells but distinct from that of BLM-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

“…The phenotype of BLM-deficient cells is characterized by a defect in the processing of Holliday junction recombination intermediates (19). BLM-catalyzed Holliday junction dissolution against crossover prevents chromosomal abnormalities as well as high frequency of spontaneous or induced sister chromatid exchanges (SCEs) seen in BLM-deficient cells (6,19). The BLM homologue in Drosophila also seems implicated in the accurate termination of gene conversion (38).…”

Section: Discussionmentioning

confidence: 99%

“…The abnormalities include gross chromosomal rearrangements, chromosome and chromatid breaks as well as triradial and quadriradial chromosomes, markers of defective mitotic recombination that are typical of the human diseases Bloom's syndrome, ataxia telangiectasia, and Fanconi's anemia, mutated in BLM, ATM, and FANC genes, respectively (6). BRCA2-deficient cells are hypersensitive to genotoxic agents that have the potential to cause DNA double-strand breaks (DSBs), implicating BRCA2 in cell cycle signaling and/or DSB repair.…”

Section: Introductionmentioning

confidence: 99%

“…The resulting intermediate can either disassemble (i.e., the newly synthesized strand can be displaced and anneal with the noninvading 3V ssDNA end to elicit noncrossover gene conversion only) or be processed to a Holliday junction intermediate to yield gene conversion with or without crossover (11,12). Homologous recombination is considered to be error free when it involves sister chromatids (9), but it can also be deleterious when it takes place between repetitive sequences, and in excess, it can promote genome instability and cause diseases (6,13,14).…”

Section: Introductionmentioning

confidence: 99%

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BRCA2 Regulates Homologous Recombination in Response to DNA Damage: Implications for Genome Stability and Carcinogenesis

2005

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BRCA2 has been implicated in the maintenance of genome stability and RAD51-mediated homologous recombination repair of chromosomal double-strand breaks (DSBs), but its role in these processes is unclear. To gain more insight into its role in homologous recombination, we expressed wild-type BRCA2 in the well-characterized BRCA2-deficient human cell line CAPAN-1 containing, as homologous recombination substrates, either direct or inverted repeats of two inactive marker genes. Whereas direct repeats monitor a mixture of RAD51-dependent and RAD51-independent homologous recombination events, inverted repeats distinguish between these events by reporting RAD51-dependent homologous recombination, gene conversion, and crossover events only. At either repeats, BRCA2 decreases the rate and frequency of spontaneous homologous recombination, but following chromosomal DSBs, BRCA2 increases the frequency of homologous recombination. At direct repeats, BRCA2 suppresses both spontaneous gene conversion and deletions, which can arise either from crossover or RAD51-independent sister chromatid replication slippage (SCRS), but following chromosomal DSBs, BRCA2 highly promotes gene conversion with little effect on deletions. At inverted repeats, spontaneous or DSB-induced crossover events were scarce and BRCA2 does not suppress their formation. From these results, we conclude that (i) BRCA2 regulates RAD51 recombination in response to the type of DNA damage and (ii) BRCA2 suppresses SCRS, suggesting a role for BRCA2 in sister chromatids cohesion and/or alignment. Loss of such control in response to estrogeninduced DNA damage after BRCA2 inactivation may be a key initial event triggering genome instability and carcinogenesis. (Cancer Res 2005; 65(10): 4117-25)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BRCA2 Regulates Homologous Recombination in Response to DNA Damage: Implications for Genome Stability and Carcinogenesis

2005

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“…Moreover, replication forks stalled at DNA damage collapse into DSBs in BRCA2-deficient cells (6). Convincingly, BRCA1-and BRCA2-deficient mouse or human cells sustain spontaneous chromatidtype aberrations, including chromosome and chromatid breaks as well as triradial and quadriradial chromosomes, markers of aberrant mitotic S-phase recombination that are typical of the human cancer predisposition diseases Bloom's syndrome, ataxia telangiectasia, and Fanconi's anemia mutated in BLM, ATM, and FANC genes, respectively (3,7).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 Regulates RAD51 Function in Response to DNA Damage and Suppresses Spontaneous Sister Chromatid Replication Slippage: Implications for Sister Chromatid Cohesion, Genome Stability, and Carcinogenesis

2005

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The breast/ovarian cancer susceptibility proteins BRCA1 and BRCA2 maintain genome stability, at least in part, through a functional role in DNA damage repair. They both colocalize with RAD51 at sites of DNA damage/replication and activate RAD51-mediated homologous recombination repair of DNA double-strand breaks (DSB). Whereas BRCA2 interacts directly with and regulates RAD51, the role of BRCA1 in this process is unclear. However, BRCA1 may regulate RAD51 in response to DNA damage or through its ability to interact with and regulate MRE11/RAD50/NBS1 (MRN) during the processing of DSBs into single-strand DNA (ssDNA) ends, prerequisite substrates for RAD51, or both. To test these hypotheses, we measured the effect of BRCA1 on the competition between RAD51-mediated homologous recombination (gene conversion and crossover) versus RAD51-independent homologous recombination [single-strand annealing (SSA)] for ssDNA at a site-specific chromosomal DSB within a DNA repeat, a substrate for both homologous recombination pathways. Expression of wild-type BRCA1 in BRCA1-deficient human recombination reporter cell lines promoted both gene conversion and SSA but greatly enhanced gene conversion. In addition, BRCA1 also suppressed both spontaneous gene conversion and deletion events, which can arise from either crossover or sister chromatid replication slippage (SCRS), a RAD51-independent process. BRCA1 does not seem to block crossover. From these results, we conclude that (a) BRCA1 regulates RAD51 function in response to the type of DNA damage and (b) BRCA1 suppresses SCRS, suggesting a role for this protein in sister chromatid cohesion/alignment. Loss of such control in response to estrogen-induced DNA damage after BRCA1 inactivation may be a key initial event that triggers genome instability and carcinogenesis. (Cancer Res 2005; 65(24): 11384-91)

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Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: Analysis of 19 patients from the BFM trials

Seidemann

Tiemann

Henze

et al. 1999

Med. Pediatr. Oncol.

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Chromosome Instability Syndromes: Lessons for Carcinogenesis

Cited by 50 publications

References 352 publications

BRCA2 Regulates Homologous Recombination in Response to DNA Damage: Implications for Genome Stability and Carcinogenesis

BRCA2 Regulates Homologous Recombination in Response to DNA Damage: Implications for Genome Stability and Carcinogenesis

BRCA1 Regulates RAD51 Function in Response to DNA Damage and Suppresses Spontaneous Sister Chromatid Replication Slippage: Implications for Sister Chromatid Cohesion, Genome Stability, and Carcinogenesis

Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: Analysis of 19 patients from the BFM trials

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