Regulation of Rad51 promoter

Hine, Christopher; Li, Hongjie; Xie, Li; Mao, Zhiyong; Seluanov, Andrei; Gorbunova, Vera

doi:10.4161/cc.29016

Cited by 25 publications

(21 citation statements)

References 39 publications

(63 reference statements)

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“…It has been recently reported that Bcl-2 and Bcl-xL are highly expressed in UM, and their inhibition had antitumor activity [ 33 ]. Moreover, Rad51 was reported to have increased activity in cancer cells compared to normal cells [ 34 ]. Therefore, Bcl-xL and Rad51 may represent important mediators of cell survival in UM, and the expression of both genes is disrupted by BRD4 targeting.…”

Section: Resultsmentioning

confidence: 99%

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells

et al. 2015

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Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.

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Section: Resultsmentioning

confidence: 99%

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells

et al. 2015

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“…RAD51 is overexpressed in the majority of human cancers [ 32 ]. Oncoproteins, such as activated Ras and SV40 T antigen, stimulate the RAD51 promoter and RAD51 expression is positively regulated by the EGR1 transcription factor [ 32 ], while p53, which is mutated or functionally inactivated in the majority of cancers, binds to and represses the RAD51 promoter [ 33 ]. Transcription factor AP2 also binds to a site in the RAD51 promoter to repress transcription in a p53-dependent manner [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Melanoma cells replicate through chemotherapy by reducing levels of key homologous recombination protein RAD51 and increasing expression of translesion synthesis DNA polymerase ζ

et al. 2017

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BackgroundThe global incidence of melanoma has been increasing faster than any other form of cancer. New therapies offer exciting prospects for improved survival, but the development of resistance is a major problem and there remains a need for additional effective melanoma therapy. Platinum compounds, such as cisplatin, are the most effective chemotherapeutics for a number of major cancers, but are ineffective on metastatic melanoma. They cause monofunctional adducts and intrastrand crosslinks that are repaired by nucleotide excision repair, as well as the more toxic interstrand crosslinks that are repaired by a combination of nuclease activity and homologous recombination.MethodsWe investigated the mechanism of melanoma resistance to cisplatin using a panel of melanoma and control cell lines. Cisplatin-induced changes in levels of the key homologous recombination protein RAD51 and compensatory changes in translesion synthesis DNA polymerases were identified by western blotting and qRT-PCR. Flow cytometry, immunofluorescence and western blotting were used to compare the cell cycle and DNA damage response and the induction of apoptosis in cisplatin-treated melanoma and control cells. Ectopic expression of a tagged form of RAD51 and siRNA knockdown of translesion synthesis DNA polymerase zeta were used to investigate the mechanism that allowed cisplatin-treated melanoma cells to continue to replicate.ResultsWe have identified and characterised a novel DNA damage response mechanism in melanoma. Instead of increasing levels of RAD51 on encountering cisplatin-induced interstrand crosslinks during replication, melanoma cells shut down RAD51 synthesis and instead boost levels of translesion synthesis DNA polymerase zeta to allow replication to proceed. This response also resulted in synthetic lethality to the PARP inhibitor olaparib.ConclusionsThis unusual DNA damage response may be a more appropriate strategy for an aggressive and rapidly growing tumour like melanoma that enables it to better survive chemotherapy, but also results in increased sensitivity of cultured melanoma cells to the PARP inhibitor olaparib.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3864-6) contains supplementary material, which is available to authorized users.

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“…P53 regulates DDB2 [40] and XPC [41], which are involved in initial events of nucleotide excision repair (NER), OGG1 [42], and MUTYH [43] in base excision repair (BER) and MSH2, MLH1, and PMS2 in mismatch repair (MMR). P53 has been reported to interact with the RAD51 promoter, albeit with minor implications on its regulation [44]. As p53 has also been postulated to physically interact with these same transcriptional targets [45][46][47], it is crucial to understand the interplay between transcription-dependent and independent functions.…”

Section: Dna Repairmentioning

confidence: 99%

How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor

Tan

Lane

2019

IJMS

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It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene targets and their consequent signaling pathways. However, transcription-independent functions of p53 also strongly define its tumor-suppressive capabilities and recent findings shed light on the molecular mechanisms hinted at by earlier efforts. This review highlights the transcription-independent mechanisms by which p53 influences the cellular response to genomic instability (in the form of replication stress, centrosome homeostasis, and transposition) and cell death. We also pinpoint areas for further investigation in order to better understand the context dependency of p53 transcription-independent functions and how these are perturbed when TP53 is mutated in human cancer.

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Regulation of Rad51 promoter

Cited by 25 publications

References 39 publications

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells

BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells

Melanoma cells replicate through chemotherapy by reducing levels of key homologous recombination protein RAD51 and increasing expression of translesion synthesis DNA polymerase ζ

How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor

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