Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage

Yoshida, Kiyotsugu; Miki, Yoshio

doi:10.1111/j.1349-7006.2004.tb02195.x

Cited by 566 publications

(435 citation statements)

References 57 publications

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“…Our studies have demonstrated that alcohol increases Brf1 expression and Pol III gene transcription to facilitate cell transformation and tumor formation (Zhang et al ., 2013; Zhong et al ., 2011, 2016). BRCA1 is a tumor suppressor (Duncan et al ., 1998; Yoshida and Miki, 2004), which is responsible for repairing damaged DNA (Chen et al ., 2011). Women with an abnormal BRCA1 gene have up to an 80% higher risk of developing breast cancer (Friendenson, 2007).…”

Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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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).…”

Section: Discussionmentioning

confidence: 99%

“…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). Whether prostate tissue is particularly susceptible to BRCA2 loss is not clear.…”

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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“…In addition, mutant BRCA2 is associated with Fanconi's anemia. Cell culture studies indicate that BRCA2 has several functions, including repair of double-strand breaks (DSBs) in DNA through homologous recombination, as well as regulation of transcription and the cell cycle (reviewed by Yoshida and Miki, 2004). It is hypothesized that tumor suppression by BRCA2 is related to its ability to repair DSBs through interaction with the RAD51 recombination enzyme (Shivji and Venkitaraman, 2004).…”

Section: Introductionmentioning

confidence: 99%

Characterizing a rat Brca2 knockout model

et al. 2006

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Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2 À/À rats are 100% viable and the vast majority live to over 1 year of age. Brca2 À/À rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2 À/À rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

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Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage

Abstract: pproximately 5% of breast cancers show a familial pattern of occurrence.

Cited by 566 publications

References 57 publications

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

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

Characterizing a rat Brca2 knockout model

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