Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

Powell, Simon N.; Kachnic, Lisa A.

doi:10.1038/sj.onc.1206678

Cited by 320 publications

(234 citation statements)

References 67 publications

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“…In support of this recent study, we observed that the hypoxic radioresistance observed after acute hypoxia (6 h Â 0.2% O 2 ; OER, 1.96 F 0.27) in HR-proficient cells was mostly lost after chronic hypoxia (72 h Â 0.2% O 2 ; OER, 1.37 F 0.05). This is consistent with the effects on radiosensitivity due to impairment of HR proficiency (21). This HR effect on radiosensitivity may in part be due to an altered number and repair of DNA-dsbs, DNA-single strand breaks, DNA-DNA interstrand cross-links, or DNA protein cross-links and requires further study (48).…”

Section: Discussionsupporting

confidence: 55%

“…For example, DNA-PK cs -deficient mice exhibit increased telomeric fusions (17), whereas overexpression of dominant-negative RAD51 is associated with centrosome aberrations and increased tumorigenicity (18). Cells expressing a dominant-negative form of RAD51 or hypomorphic alleles of BRCA2 show impaired HR (19), and cells deficient in HR or NHEJ have a reduced capacity for DNA-dsb rejoining (20,21). Therefore, maintaining error-free repair is imperative to preserve genomic stability (4).…”

Section: Introductionmentioning

confidence: 99%

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Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

et al. 2008

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Hypoxic and/or anoxic tumor cells can have increased rates of mutagenesis and altered DNA repair protein expression. Yet very little is known regarding the functional consequences of any hypoxia-induced changes in the expression of proteins involved in DNA double-strand break repair. We have developed a unique hypoxic model system using H1299 cells expressing an integrated direct repeat green fluorescent protein (DR-GFP) homologous recombination (HR) reporter system to study HR under prolonged chronic hypoxia (up to 72 h under 0.2% O 2 ) without bias from altered proliferation, cell cycle checkpoint activation, or severe cell toxicity. We observed decreased expression of HR proteins due to a novel mechanism involving decreased HR protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O 2 as measured by the DR-GFP reporter system. This decrease in functional HR resulted in increased sensitivity to the DNA cross-linking agents mitomycin C and cisplatin but not to the microtubule-interfering agent, paclitaxel. Chronically hypoxic H1299 cells that had decreased functional HR were relatively radiosensitive [oxygen enhancement ratio (OER), 1.37] when compared with acutely hypoxic or anoxic cells (OER, 1.96-2.61). Using CAPAN1 cells isogenic for BRCA2 and siRNA to RAD51, we confirmed that the hypoxia-induced radiosensitivity was due to decreased HR capacity. Persistent down-regulation of HR function by the tumor microenvironment could result in low-fidelity DNA repair and have significant implications for response to therapy and genetic instability in human cancers. [Cancer Res 2008;68(2):605-14]

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

et al. 2008

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“…For example, the encoded BRCA2 protein is involved in DNA repair, transcription, and cell cycle control (Davies et al, 2001;Venkitaraman, 2002;Powell et al, 2003;Yoshida and Miki, 2004). BRCA2 interacts directly with RAD51, which is an essential protein for error-free double-strand DNA break repair by homologous recombination (Sharan et al, 1997;Wong et al, 1997;Xia et al, 2001;Pellegrini et al, 2002;Venkitaraman, 2002;Jackson, 2002;Powell et al, 2003). BRCA2 regulates both the intracellular localisation and DNA-binding ability of RAD51, and therefore loss of this control following BRCA2 inactivation may be a key event leading to genomic instability and carcinogenesis (Davies et al, 2001;Jackson, 2002;Yoshida and Miki, 2004).…”

Section: Discussionmentioning

confidence: 99%

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer

et al. 2007

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Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages p55 years, highlighting the potential importance of this gene in prostate cancer susceptibility. To examine the role of protein-truncating BRCA2 mutations in relation to early-onset prostate cancer in a US population, 290 population-based patients from King County, Washington, diagnosed at ages o55 years were screened for germline BRCA2 mutations. The coding regions, intron -exon boundaries, and potential regulatory elements of the BRCA2 gene were sequenced. Two distinct protein-truncating BRCA2 mutations were identified in exon 11 in two patients. Both cases were Caucasian, yielding a mutation prevalence of 0.78% (95% confidence interval (95%CI) 0.09 -2.81%) and a relative risk (RR) of 7.8 (95%CI 1.8 -9.4) for early-onset prostate cancer in white men carrying a protein-truncating BRCA2 mutation. Results suggest that protein-truncating BRCA2 mutations confer an elevated RR of early-onset prostate cancer. However, we estimate that o1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations. British Journal of Cancer (2007) (BCLC, 1999;Johannsson et al, 1999;Eerola et al, 2001;Tulinius et al, 2002;Bermejo and Hemminki, 2004;van Asperen et al, 2005), kin-cohort studies of cancer incidence among relatives of population-based breast or ovarian cancer cases (Loman et al, 2003;Risch et al, 2006), as well as studies of populations who harbour founder BRCA2 mutations (Sigurdsson et al, 1997;Struewing et al, 1997, Kirchhoff et al, 2004 suggest that men who carry a diseaseassociated BRCA2 allele have an increased relative risk (RR) of prostate cancer (two-to five-fold elevation). Two of the family studies in which data were stratified on age at diagnosis of prostate cancer reported that the RR was even higher (seven-to eight-fold increase) in men diagnosed before age 65 years (BCLC, 1999;van Asperen et al, 2005). These findings suggest that proteintruncating BRCA2 mutations may play a role in prostate cancer susceptibility. However, the majority of studies that have investigated the role of BRCA2 mutations in hereditary prostate cancer (HPC) families, which usually include men diagnosed with prostate cancer at younger ages, have reported no diseaseassociated mutations (Wilkens et al, 1999;Gayther et al, 2000;Sinclair et al, 2000;Agalliu et al, 2007).To date, only one study has assessed the contribution of BRCA2 mutations in early-onset sporadic prostate cancer (Edwards et al, 2003). In a case series of 263 men in the UK diagnosed with prostate cancer at younger ages (p55 years), and who were not selected on the basis of either breast or prostate cancer family history, the prevalence of protein-truncating BRCA2 mu...

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“…It is not clear whether DSG repair entails any kind of processing of the dsDNA-ssDNA iunction. In the limited studies that have been performed so far on different BRCA alleles, there appears to be a correlation between defective tumor suppressor function and loss of HR/DSBR function [90][91][92], suggesting that the HR functions of BRCA1 and BRCA2 contribute to tumor suppression.…”

Section: Role Of Brca1 and Brca2 In Hr Regulationmentioning

confidence: 99%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

Cited by 320 publications

References 67 publications

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

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