Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites

Bindra, Ranjit S.; Glazer, Peter M.

doi:10.4161/cbt.5.10.3454

Cited by 31 publications

(43 citation statements)

References 37 publications

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“…Definition of the relevant subset is ongoing, but at least one additional FA gene, FANCB, was noted by the DiMaio Laboratory as repressed in response to E2-mediated E7 repression in HeLa cells (Johung et al, 2007;supplementary data). Published reports on the E2F-dependent repression of Rad51 and BRCA1, specifically during hypoxia, (Oberley et al, 2003;Bindra and Glazer, 2006;Bindra et al, 2007), together with the repression of these two molecules in our microarray experiments (data not shown) and in Figure 2a, respectively, may imply coordination with a wider network of DNA repair pathways. With regard to human cancers exhibiting high E2F activity and rapid cell proliferation, the deregulation of individual, but not necessarily multiple, components of the system may be responsible for insufficient DNA repair, high mutational frequencies and carcinogenesis.…”

Section: Discussionmentioning

confidence: 90%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.

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Section: Discussionmentioning

confidence: 90%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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“…Previous work has shown that E7 prevents down-regulation of BRCA1 and RAD51 in hypoxia by disrupting p130/E2F4 binding to the respective promoters (11)(12)(13)(14)(15). E7 expression was found to confer resistance to PARP inhibition in hypoxic cells (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…In prior work, we found that hypoxia suppresses HDR in human cells via transcriptional down-regulation of BRCA1 and RAD51 (11)(12)(13)(14)(15). Hence, we hypothesized that cancer cells in hypoxia, with acquired deficiency in HDR, might have increased sensitivity to PARP inhibition.…”

mentioning

confidence: 99%

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

Hegan¹,

Lü²,

Stachelek³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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188

111

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Inhibitors of poly(ADP-ribose) polymerase (PARP) are in clinical trials for cancer therapy, on the basis of the role of PARP in recruitment of base excision repair (BER) factors to sites of DNA damage. Here we show that PARP inhibition to block BER is toxic to hypoxic cancer cells, in which homology-dependent repair (HDR) is known to be down-regulated. However, we also report the unexpected finding that disruption of PARP, itself, either via chemical PARP inhibitors or siRNAs targeted to PARP-1, can inhibit HDR by suppressing expression of BRCA1 and RAD51, key factors in HDR of DNA breaks. Mechanistically, PARP inhibition was found to cause increased occupancy of the BRCA1 and RAD51 promoters by repressive E2F4/p130 complexes, a pathway prevented by expression of HPV E7, which disrupts p130 activity, or by siRNAs to knock down p130 expression. Functionally, disruption of p130 by E7 expression or by siRNA knockdown also reverses the cytotoxicity and radiosensitivity associated with PARP inhibition, suggesting that the down-regulation of BRCA1 and RAD51 is central to these effects. Direct measurement of HDR using a GFP-based assay demonstrates reduced HDR in cells treated with PARP inhibitors. This work identifies a mechanism by which PARP regulates DNA repair and suggests new strategies for combination cancer therapies.DNA repair | hypoxia P oly(ADP-ribose) polymerases (PARPs) comprise a family of enzymes that catalyze ADP ribosylation of a variety of cellular factors (1-4). PARP-1 is thought to play a key role in DNA repair, primarily by modifying chromatin factors at sites of DNA damage and thereby recruiting repair factors. Inhibitors of PARP have attracted interest for cancer therapy because cancer cells deficient in BRCA1 or BRCA2 due to inactivating mutations are sensitive to PARP inhibition (5-8). This has been attributed to the role of PARP in recruiting base excision repair (BER) factors that remove damaged bases and fix single-strand breaks (SSBs) (1). SSBs persisting into S-phase produce replication fork collapse, requiring BRCA1-and BRCA2-mediated homology-dependent repair (HDR) for resolution (5, 9, 10).In prior work, we found that hypoxia suppresses HDR in human cells via transcriptional down-regulation of BRCA1 and RAD51 (11-15). Hence, we hypothesized that cancer cells in hypoxia, with acquired deficiency in HDR, might have increased sensitivity to PARP inhibition. Work presented here confirms this hypothesis, showing that PARP inhibitors are more cytotoxic to hypoxic than to normoxic cells. Because hypoxia causes BRCA1 and RAD51 down-regulation by stimulating E2F4/p130 occupancy of the BRCA1 and RAD51 promoters, we asked whether disruption of p130 function via expression of human papillomavirus (HPV) E7 would reverse the sensitivity of hypoxic cells to PARP inhibition. We found that E7 expression, as predicted, does confer resistance to PARP inhibitors on hypoxic cells, but surprisingly, it also blocks the toxicity of PARP inhibition in normoxic cells.As a basis for this effect, we present eviden...

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“…Furthermore, there is a paucity of evidence to link these BRCA1 regulators to defined BRCA1-dependent phenotypes. Metastasis-associated tumor antigen 1 (MTA1) has been implicated in the transcriptional repression of BRCA1 and in abnormal centrosome number and chromosomal instability (30), and E2F4 and the pocket proteins p130/p107 bind the BRCA1 promoter and repress its basal transcription, thereby regulating cell growth (97). In these studies, we demonstrate that HOXA9 directly and positively modulates BRCA1 transcription, thereby restricting the abnormal growth, survival, and stress response of breast cancer cells and nonmalignant MECs in culture and in vivo.…”

Section: Discussionmentioning

confidence: 99%

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

Gilbert¹,

Mouw²,

Unger³

et al. 2010

J. Clin. Invest.

103

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Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.

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Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites

Cited by 31 publications

References 37 publications

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

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