Centrosome Amplification and a Defective G2–M Cell Cycle Checkpoint Induce Genetic Instability in BRCA1 Exon 11 Isoform–Deficient Cells

Xu, Xiaoling; Weaver, Zoë; Linke, Steven P.; Li, Cuiling; Gotay, Jessica; Wang, Xin Wei; Harris, Curtis C.; Ried, Thomas; Deng, Chu‐Xia

doi:10.1016/s1097-2765(00)80466-9

Cited by 753 publications

(636 citation statements)

References 35 publications

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“…HTC75 cells expressing the truncated forms of Tankyrase 1 and the isogenic control cell lines, MOCK and TANK-1, were transfected with BRCA1-or BRCA2-silencing plasmids and the number of centrosomes analysed by immunofluorescence. We observed a significant increase in the number of cells with centrosome amplification after silencing of BRCA1 or BRCA2 alone compared to controls, consistent with previous studies (Figures 4a and b; Tutt et al, 1999;Xu et al, 1999). However, this phenotype was considerably exacerbated in cells with silenced BRCA1 or BRCA2 in the presence of the ARCV Tankyrase 1 mutant (Figures 4a and b).…”

Section: Resultssupporting

confidence: 91%

“…BRCA1-and BRCA2-deficient cells have also been previously shown to display centrosome amplification and furthermore BRCA1 has been shown to interact with the centrosome in M-phase cells (Tutt Xu et al, 1999). Therefore, we investigated whether the synthetic lethality between BRCA and Tankyrase 1 was because of the exacerbation of known mitotic phenotypes associated with BRCA deficiency.…”

Section: Resultsmentioning

confidence: 99%

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Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

et al. 2009

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The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-offunction mutations in either BRCA1 or BRCA2 strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCAassociated cancers.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

et al. 2009

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“…BRCA1 has been implicated in a variety of biological settings, including double-strand break repair and homologous recombination in mitotic cells (Cressman et al, 1999a;Snouwaert et al, 1999), and DNA strand exchange in meiotic cell division Cressman et al, 1999a;Scully et al, 1997b;Zabludo et al, 1996). Depending on the severity of the deletion, murine embryos lacking Brca1 die between 7.5 and 11 days of development due to accumulated DNA defects .…”

Section: Discussionmentioning

confidence: 99%

“…Testis is a site of signi®cant BRCA1 expression (Lane et al, 1995;Scully et al, 1997b) due to a presumed role for the protein in homologous strand exchange (Snouwaert et al, 1999;Zabludo et al, 1996). Antibodies were the generous gift of Drs C Wilson and D Slamon (UCLA School of Medicine, Los Angeles, CA, USA) and have been described elsewhere (Wilson et al, 1997(Wilson et al, , 1999.…”

Section: Placement Of a Brcamentioning

confidence: 99%

“…In keeping with the high rate of TP53 mutation in BRCA1-derived human cancers (Crook et al, 1998;Phillips et al, 1999), mice with mutations in Brca1 develop tumors which show allelic loss of Trp53 , and bigenic mice with mutations in both Brca1 +/7 and Trp53 7/7 are speci®cally prone to the development of breast cancers (Cressman et al, 1999b;Xu et al, 1999). Paradoxically, human cells that lack BRCA1 are very di cult to obtain and doubly mutant mouse cells grow poorly due to high rates of chromosomal loss associated with defective G2 checkpoint control .…”

Section: Introductionmentioning

confidence: 98%

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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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Emerging roles of BRCA1 in transcriptional regulation and DNA repair

1999

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BRCA1 was the first breast cancer susceptibility gene to be identified and cloned. In individuals from high-risk families, mutations in BRCA1 increase the lifetime risk of developing breast cancer eight to tenfold, compared to the general population. How the BRCA1 protein product normally functions to suppress tumor formation and how defects in the gene can ultimately lead to breast cancer have been the focus of intense scrutiny by the scientific and medical communities. BRCA1 has intrinsic transactivation activity and is able to activate the p21 promoter. In addition, BRCA1 is linked to a number of genes involved in transcriptional regulation, including CtIP, c-Myc, the RNA holoenzyme complex, and the histone deacetylase complex. Moreover, BRCA1 is essential for cellular response to DNA damage repair. Inactivation of Brca1 in mouse embryonic stem and fibroblast cells results in increased cell sensitivity to DNA-damaging agents. In human cells, BRCA1 binds to both Rad50 and Rad51 and colocalizes with these proteins at repair foci. Part of BRCA1's response to DNA damage may in fact be corroborated through transcriptional regulation. The expression of GADD45, a DNA damage-responsive gene, is increased immediately after induction of BRCA1. Recently, BRCA1 was shown to repress estradiol (E2)-responsive ER-alpha-mediated transcriptional activity, potentially linking the multiple functions of BRCA1 to specific tissue targets. These recent developments in BRCA1 function are an encouraging step toward understanding the role of BRCA1 in breast cancer formation.

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Centrosome Amplification and a Defective G2–M Cell Cycle Checkpoint Induce Genetic Instability in BRCA1 Exon 11 Isoform–Deficient Cells

Cited by 753 publications

References 35 publications

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

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

Emerging roles of BRCA1 in transcriptional regulation and DNA repair

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