The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang, Junran; Powell, Simon N.

doi:10.1158/1541-7786.mcr-05-0192

Cited by 182 publications

(154 citation statements)

References 91 publications

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“…To test this idea, we carried out colony formation assays using wild-type and SMCHD1 KO cells treated with Zeocin. The BRCA1 KO cells were also included as a positive control, as it has been found that BRCA1-deficient cells are sensitive to ionizing radiation and drugs that produce DSBs (32)(33)(34)(35). Consistent with previous studies, exposure to Zeocin led to dose-dependent cell death in BRCA1 KO cells.…”

Section: Generation Of Smchd1 Knock-out Hela Cells Using the Crispr/ mentioning

confidence: 53%

Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage

Tang

Zhang

et al. 2014

Journal of Biological Chemistry

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Background:The role of SMCHD1 in DNA damage response is largely unknown. Results: SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 compromised cell survival, and decreased the efficiency of non-homologous end joining (NHEJ) while elevating the efficiency of homologous recombination (HR). Conclusion: SMCHD1 regulates both NHEJ and HR. Significance: Our findings should further understanding of how cells adopt different repair pathways.

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Section: Generation Of Smchd1 Knock-out Hela Cells Using the Crispr/ mentioning

confidence: 53%

Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage

Tang

Zhang

et al. 2014

Journal of Biological Chemistry

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“…The reasons for this reduction are currently unclear. It is possible that ERa expression in the tumor initiation stages facilitates cell proliferation but at later stages it may restrict cell proliferation, as E2 could induce DNA damage that BRCA1-mutant cells cannot repair because of their deficiency in the multiple DNA damage repairing pathways (Deng and Wang, 2003;Zhang and Powell, 2005). It is conceivable that these ERa-positive cells gradually lose their ERa expression due to epigenetic modifications, which allows them to proliferate leading to the formation of full-grown tumors.…”

Section: Discussionmentioning

confidence: 99%

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Xiao

et al. 2007

Oncogene

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Estrogen and its receptor alpha (ERa) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERa-negative, challenging the link between BRCA1 and estrogen/ERa in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ERa-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ERa signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERasignaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

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“…BRCA1 encodes a 1,863-amino-acid protein that associates with a multitude of proteins involved in cell cycle checkpoint regulation, DNA repair, transcription, chromatin remodeling, and ubiquitination (9)(10)(11)(12)(13), suggesting that BRCA1 plays a critical role in the cellular response to DNA damage. However, the exact mechanism by which BRCA1 functions in the DNA damage response is not completely understood, partly due to the paucity of human BRCA1-null cell lines available for study.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation

DelloRusso

Welcsh

Wang

et al. 2007

Molecular Cancer Research

101

109

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The breast and ovarian cancer susceptibility gene BRCA1 plays a major role in the DNA damage response pathway. The lack of well-characterized human BRCA1-null cell lines has limited the investigation of BRCA1 function, particularly with regard to its role in ovarian cancer. We propagated a novel BRCA1-null human ovarian cancer cell line UWB1.289 from a tumor of papillary serous histology, the most common form of ovarian carcinoma. UWB1.289 carries a germline BRCA1 mutation within exon 11 and has a deletion of the wild-type allele. UWB1.289 is estrogen and progesterone receptor negative and has an acquired somatic mutation in p53, similar to the commonly used BRCA1-null breast cancer cell line HCC1937. We used ionizing radiation to induce DNA damage in both UWB1.289 and in a stable UWB1.289 line in which wild-type BRCA1 was restored. We examined several responses to DNA damage in these cell lines, including sensitivity to radiation, cell cycle checkpoint function, and changes in gene expression using microarray analysis. We observed that UWB1.289 is sensitive to ionizing radiation and lacks cell cycle checkpoint functions that are a normal part of the DNA damage response. Restoration of wild-type BRCA1 function in these cells partially restores DNA damage responses. Expression array analysis not only supports this partial functional correction but also reveals interesting new information regarding BRCA1-positive regulation of the expression of claudin 6 and other metastasis-associated genes and negative regulation of multiple IFN-inducible genes. (Mol Cancer Res 2007;5(1):35 -45)

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The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Cited by 182 publications

References 91 publications

Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage

Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) Promotes Non-homologous End Joining and Inhibits Homologous Recombination Repair upon DNA Damage

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation

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