Alterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability

Bindra, Ranjit S.; Schaffer, Paul J.; Meng, Alice; Woo, Jennifer M.P.; Måseide, Kårstein; Roth, Matt E.; Lizardi, Paul M.; Hedley, David W.; Bristow, Robert G.; Glazer, Peter M.

doi:10.1196/annals.1339.049

Cited by 69 publications

(42 citation statements)

References 14 publications

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“…We have shown previously that the tumor microenvironmental stress of hypoxia induces a shift in binding from activating E2F1 to repressive E2F4 complexes to the BRCA1 promoter, resulting in BRCA1 mRNA downregulation, consequent suppression of recombinational repair activity. 26,27,38 The findings presented here highlight the complexity of regulation of critical tumor suppressor genes such as BRCA1 by the E2F family of transcription factors. Further elucidation of the mechanism(s) by which E2Fs, pocket proteins, and other potential factors regulate BRCA1 expression at the adjacent E2F sites in the proximal promoter, both in log-phase cells as well as in response to various cell stresses, will provide further insight into the regulation of tumor suppressor gene function in both normal and cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

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

Bindra¹,

Glazer²

2006

Cancer Biology & Therapy

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The BRCA1 gene is rarely mutated in sporadic tumors, although numerous studies suggest that the expression of this critical tumor suppressor gene is frequently downregulated in tumors derived from a wide range of tissues. However, little is known regarding the mechanisms by which BRCA1 is transcriptionally regulated in human cells in vivo. We have shown recently that the tumor microenvironmental stress of hypoxia induces an E2F-dependent repression of BRCA1 in cancer cells. Here, we report that multiple E2Fs and associated factors bind the BRCA1 promoter at two adjacent E2F sites in the proximal promoter region of the gene, as detected by quantitative chromatin immunoprecipitation (ChIP) analysis. Intriguingly, our data suggest that E2F1 and E2F4 bind the BRCA1 proximal promoter simultaneously at the two E2F sites, although E2F4 appears to be the predominant E2F bound in log-phase cells. In contrast to previous studies, we have also detected promoter occupancy by the pocket proteins p130 and p107, but not Rb, our data indicate that E2F4 and p130/p107 complexes basally repress the BRCA1 promoter. We find that binding by these factors requires both intact E2F sites, which suggests a novel interaction between adjacent promoter elements. Taken together, these findings provide an enhanced molecular portrait of BRCA1 transcriptional regulation by E2Fs and pocket proteins, they enhance our understanding of regulation by repressive E2F complexes at target genes in vivo. Furthermore, the identification of E2F4 and p130/ p107 complexes as basal repressors of BRCA1 expression may facilitate the development of strategies based on disruption of these interactions to rescue BRCA1 expression in human tumors.

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Section: Discussionmentioning

confidence: 99%

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

Bindra¹,

Glazer²

2006

Cancer Biology & Therapy

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“…Evidence suggests that ROS increases HIF1A by directly inhibiting PHD catalytic activity (Cash et al 2007, Kaelin & Ratcliffe 2008. Finally, reports have also suggested that hypoxia can act independently of the HIF1A transcription factor (Bindra et al 2005, Arany et al 2008, Fujisaka et al 2013.…”

Section: Introductionmentioning

confidence: 99%

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Yalu¹,

Oyesiji²,

Eisenberg³

et al. 2015

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Hypoxia-inducible factor 1 alpha (HIF1A) and endothelin 2 (EDN2) are transiently expressed during the same time window in the developing corpus luteum (CL). In this study, we sought to investigate the involvement of LH/cAMP, reactive oxygen species (ROS), and a hypoxia-mimetic compound (CoCl 2 ) on HIF1A expression and how it affected EDN2 levels, using transformed human granulosa cells (thGCs) and primary bovine granulosa cells (GCs). CoCl 2 elevated HIF1A protein levels in thGCs in a dose-dependent manner. Forskolin alone had no significant effect; however, forskolin and CoCl 2 together further induced HIF1A protein and EDN2 mRNA expression in thGCs. Similarly, in primary GCs, LH with CoCl 2 synergistically augmented HIF1A protein levels, which resulted in higher expression of EDN2 and another well-known hypoxia-inducible gene, VEGF (VEGFA). Importantly, LH alone elevated HIF1A mRNA but not its protein. The successful knockdown of HIF1A in thGCs using siRNA abolished hypoxia-induced EDN2 and also the additive effect of forskolin and CoCl 2 . We then examined the roles of ROS in thGCs: hydrogen peroxide (20 and 50 mM) elevated HIF1A protein as well as the expression of EDN2, implying that induction of HIF1A protein levels is sufficient to stimulate the expression of EDN2 (and VEGF) in normoxia. A broad-range ROS scavenger, butylated hydroxyanisole, inhibited CoCl 2 -induced HIF1A protein with a concomitant reduction in the mRNA expression of EDN2 and VEGF in thGCs. The results obtained in this study suggest that HIF1A, induced by various stimuli, is an essential mediator of EDN2 mRNA expression. The results may also explain the rise in the levels of HIF1A-dependent genes (EDN2 and VEGF) in the developing CL.

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“…However, this hypoxic radioprotection may be partially offset by the downregulation of genes involved in HR repair, one of the two major double-strand break repair pathways, for reasons that are still unclear. [31][32][33][34][35][36] Thus, therapeutically targeting the other double strand-break repair pathway (i.e., NHEJ) may decrease the radioresistance of hypoxic cells in the tumor and increase the therapeutic gain (Fig. 4).…”

Section: New Strategiesmentioning

confidence: 99%

Enhancing radiosensitivity: Targeting the DNA repair pathways

Jorgensen

2009

Cancer Biology & Therapy

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Radiotherapy is very effective in local control of cancerous tumors, but its curative potential is often limited by intrinsic radioresistance of the tumor cells. Since DNA repair pathways remove radiation-induced DNA lesions and protect cells from lethality, these pathways represent potential therapeutic targets to radiosensitize tumors. In order to achieve a therapeutic gain, however, there must be a differential between tumor and normal cells that can be exploited to preferentially target the DNA repair of the tumor, while sparing surrounding normal tissues, and this has represented a significant challenge to progress. Nevertheless, recent advances in our understanding of DNA repair mechanisms and tumor biology, on both the biochemical and genetic levels, have identified molecular differentials that may increase tumor specificity. This mechanistic insight suggests new strategies for radiotherapeutic targeting of DNA repair. Some of these strategies are reviewed here, including synthetic lethal, replicative stress, cell cycle and hypoxia-based approaches. The example of PARP1 inhibitor use in BRCA1 and 2 mutated breast cancer therapy is discussed, and future directions and challenges are explored.

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Alterations in DNA Repair Gene Expression under Hypoxia: Elucidating the Mechanisms of Hypoxia‐Induced Genetic Instability

Cited by 69 publications

References 14 publications

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

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

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Enhancing radiosensitivity: Targeting the DNA repair pathways

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