BRCA1-BARD1 Complexes Are Required for p53Ser-15 Phosphorylation and a G1/S Arrest following Ionizing Radiation-induced DNA Damage

Fabbro, Megan; Savage, Kienan I.; Hobson, Karen; Deans, Andrew J.; Powell, Simon N.; McArthur, Grant A.; Khanna, Kum Kum

doi:10.1074/jbc.m405372200

Cited by 143 publications

(110 citation statements)

References 63 publications

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“…Supporting the idea that the 3 0 processing machinery is interconnected with the p53 pathway, it has been shown that Rbbp6, a p53-binding protein, and Ku-70 subunit of DNA-PK, which is involved in the BARD1-mediated phosphorylation of p53 Ser15 upon DNA damage (Fabbro et al, 2004), are part of the pre-mRNA 3 0 processing complex ). Other tumor suppressors, such as CSR1 and Cdc73, have also been shown to functionally associate with 3 0 processing factors, such as CPSF3 (Zhu et al, 2009) and CPSF/ CstF (Rozenblatt-Rosen et al, 2009).…”

Section: Discussionmentioning

confidence: 96%

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

et al. 2011

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The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3 0 cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3 0 processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3 0 cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3 0 cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3 0 cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3 0 processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3 0 RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network.

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Section: Discussionmentioning

confidence: 96%

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

et al. 2011

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“…Phosphorylation of BRCA1 on these sites is closely linked to S-phase and G2/M checkpoints (Xu et al, 2001. Several studies also showed that BRCA1 is required for optimal levels of ATM-dependent phosphorylation of p53, c-Jun, Nbs1, Chk2, CtIP and SMC1, although the BRCA1 dependence of some of these phosphorylation events is controversial (Foray et al, 2003;Fabbro et al, 2004;Kitagawa et al, 2004). Kitagawa et al (2004) also showed that BRCA1 is required for focus formation by autophosphorylated ATM.…”

Section: Likely Candidates For Inactivators and Activators Of Atmmentioning

confidence: 99%

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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“…The proper G1/S checkpoint regulation following DNA damage is mainly due to the p53-mediated induction of p21 waf1 and it has been proposed that BRCA1 expression is necessary for p53 and p21 induction following ionizing radiation (Fabbro et al, 2004), suggesting that the absence of BRCA1 could influence the G1/S cell cycle progression after DNA damage (Fabbro et al, 2004). We thus evaluated the expression of p21 and p53 in parental and YHA6 and 7 MCF-7 cells untreated or exposed for 24 h to cisplatin or bleomycin.…”

Section: Mcf-7 Cells Overexpressing the Hmga1 Protein Are More Sensitmentioning

confidence: 99%

HMGA1 protein expression sensitizes cells to cisplatin-induced cell death

et al. 2005

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HMGA1 proteins belong to a family of nonhistone chromatin proteins able to bind DNA in AT-rich regions and to interact with various transcription factors thus enhancing or inhibiting gene transcription by acting as architectural proteins. Although their expression is very low or absent in many adult tissues, HMGA1 proteins have been frequently found to be upregulated in human cancers and are expressed at high levels during embryogenesis, suggesting they could have a role in highly proliferating cells. We have previously demonstrated that HMGA1 expression in primary breast cancer and mammary carcinoma derived cell lines inversely correlated with BRCA1 expression and that HMGA1 is able to downregulate the expression of BRCA1 gene by binding directly to its promoter region. Being BRCA1 protein expression strictly linked to the DNA repair activity of the cell, we investigated whether HMGA1 expression was able to influence cellular responses to DNA damage. Here, we report that high expression levels of HMGA1 proteins in MCF-7 or mouse embryonic stem cells results in diminished BRCA1 expression and enhanced sensitivity to Cisplatin and Bleomycin. The increased DNA damageinduced cell death in HMGA1-expressing cells is likely due to a diminished cellular DNA repair activity. Therefore, we propose that high expression of HMGA1 protein in human malignant neoplasias, acting on BRCA1 expression, could contribute to the progression of malignant transformation influencing the response of the cells to the damaged DNA.

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BRCA1-BARD1 Complexes Are Required for p53Ser-15 Phosphorylation and a G1/S Arrest following Ionizing Radiation-induced DNA Damage

Cited by 143 publications

References 63 publications

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

HMGA1 protein expression sensitizes cells to cisplatin-induced cell death

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