BRCA1 Required for Transcription-Coupled Repair of Oxidative DNA Damage

Gowen, Lori C.; Avrutskaya, Anna V.; Latour, Anne M.; Koller, Beverly H.; Leadon, Steven A.

doi:10.1126/science.281.5379.1009

Cited by 464 publications

(308 citation statements)

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“…In an investigation of oxidative damage repair in cells with BRCA1 mutations, an increase in damage was found in homozygous but not heterozygous mutated cells. 1 In addition, mouse embryos engineered for homozygous BRCA2 mutations displayed radiosensitivity, whereas embryos with heterozygous mutations did not. 2 There are a number of possible reasons for the disparity between our results and these previously reported data.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo and in vitro studies suggest that homozygous mutations in either BRCA1 or BRCA2 result in a deficiency in processing of DNA damage repair and radiosensitivity. 1,2 Whether individuals heterozygous for a BRCA1 or BRCA2 mutation exhibit impaired recognition and processing of DNA damage is unknown. This is a relevant question for the management of individuals with a germline BRCA mutation, in that a deficiency in cellular DNA damage repair could increase the risk of a normal tissue injury following ionizing radiation or increase the risk of radiation-induced breast carcinogenesis.…”

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confidence: 99%

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Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Buchholz

Hussain

et al. 2001

Intl Journal of Cancer

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The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. Key words: radiation; chromatid breaks; fibroblasts; clonogenic survivalThe carcinogenic risks of mammography and ionizing radiation treatments for individuals with a BRCA1 or BRCA2 germline mutation have not been determined. In vivo and in vitro studies suggest that homozygous mutations in either BRCA1 or BRCA2 result in a deficiency in processing of DNA damage repair and radiosensitivity. 1,2 Whether individuals heterozygous for a BRCA1 or BRCA2 mutation exhibit impaired recognition and processing of DNA damage is unknown. This is a relevant question for the management of individuals with a germline BRCA mutation, in that a deficiency in cellular DNA damage repair could increase the risk of a normal tissue injury following ionizing radiation or increase the risk of radiation-induced breast carcinogenesis. Furthermore, it may also impact the sensitivity of nonbreast and non-ovarian tissues to mutagenesis and carcinogenesis. We have experience with 2 in vitro assays that study cellular radiosensitivity. The radiation-induced chromatid break assay has been shown to correlate with the risk of developing lung cancer, brain tumors and most recently with bilateral breast cancer. 3,4,5 We have also previously shown that fibroblast clonogenic cell survival curves reflect intrinsic cellular radiosensitivity and correlate with the probability of normal tissue injury following ionizing radiation treatment. 6,7 Our study describes the results of in vitro radiosensitivity assays performed on fibroblasts and lymphocytes obtained from individuals with a sequence-proven mutation in either BRCA1 or BRCA2. These preliminary data suggest that a germline mutation in BRCA1 or BRCA2 is associated with increased radiosensitivity compatible with haplotype insufficiency. MATERIAL AND METHODS Study populationOur study was conducted under protocols approved by the Institutional Review Board of the University of Texas M. D. Anderson Cancer Center, Houston, TX. All study participants provided informed consent and participated voluntarily. A total of 7 individuals with sequence-p...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Buchholz

Hussain

et al. 2001

Intl Journal of Cancer

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“…Subsequent studies have documented roles for BRCA1 in two highly specialized DNA repair processes: (1) transcription coupled DNA repair (TCR); and (2) homology-directed repair (HDR). Studies of both Brca1 À/À mouse embryo fibroblasts (MEFs) and a human breast cancer cell line (HCC1937) that contains a single mutant BRCA1 allele (5682insC) revealed that BRCA1 deficient cells have a defect in TCR of oxidative DNA damage caused by ionizing radiation (Gowen et al, 1998;Abbott et al, 1999). Thus, when strand-specific DNA repair was evaluated for several genes, including DHFR (dihydrofolate reductase), BRCA1 competent cells exhibited greater ability to repair the transcribed strand than the non-transcribed strand; whereas BRCA1 deficient cells showed equal repair of both strands, with a reduced rate of repair of the transcribed strand, as compared with BRCA1 competent cells.…”

Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…BRCA1 protein has been demonstrated to respond to DNA damaging agents by increased phosphorylation and movement out of nuclear dot structures Gowen et al, 1998;Scully et al, 1997a). To test whether proteins expressed from the TgN´BRCA1-B transgene respond to DNA damaging agents, we isolated fresh tissues and exposed them to ionizing radiation for various time periods.…”

Section: Placement Of a Brcamentioning

confidence: 99%

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

Lane¹,

Lin²,

Brown

et al. 2000

Oncogene

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We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN´BRCA1 GEN ). We ®nd that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DNA damage. Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1 DexllSA ). Brca1 7/7 ; TgN´BRCA1 GEN bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein. Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system. Oncogene (2000) 19, 4085 ± 4090.

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BRCA1 Required for Transcription-Coupled Repair of Oxidative DNA Damage

Cited by 464 publications

References 23 publications

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

BRCA1 gene in breast cancer

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

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