The RAD51 protein supports homologous recombination by an exchange mechanism in mammalian cells 1 1Edited by J. Karn

Arnaudeau, Catherine; Helleday, Thomas; Jenssen, Dag

doi:10.1006/jmbi.1999.2856

Cited by 63 publications

(47 citation statements)

References 47 publications

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“…As the inhibition of HDAC1/2/3 downregulates RAD51 and FANCD2, and both protect cancer cells against temozolomide (15,39) because of their role in HR (13,40), the effect of HDACi on HR was assayed. Inhibition of class I HDACs significantly decreased HR activity in both D05 and A375 melanoma cell lines upon DSB induction (Fig.…”

Section: Inhibition Of Hdac1/2/3 Downregulates Rad51 and Fancd2mentioning

confidence: 99%

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

et al. 2016

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DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo. HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O 6 -methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC-and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. Ó2016 AACR.

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Section: Inhibition Of Hdac1/2/3 Downregulates Rad51 and Fancd2mentioning

confidence: 99%

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

et al. 2016

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“…Mouse embryos blastocytes deleted for RAD51 gene are highly sensitive to ionizing radiation (IR) (Tsuzuki et al, 1996). In addition, a mild overexpression of Rad51 in mammalian cells leads to increased spontaneous recombination frequency (Vispe et al, 1998;Arnaudeau et al, 1999) and increased homologous recombination following ionizing radiation treatment (Lambert and Lopez, 2000). Moreover, it results in an increased resistance to IR when cells are in S phase (Vispe et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

DNA damage induce γ-tubulin–RAD51 nuclear complexes in mammalian cells

et al. 2005

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Rad51 protein plays an essential role in recombination repair of DNA double-strand breaks and DNA crosslinking adducts. It is part of complexes which can vary with the stage of the cell cycle and the nature of the DNA lesions. During a search for Rad51-associated proteins in CHO nuclear extracts of S-phase cells by mass spectrometry of proteins immunoprecipitated with Rad51 antibodies, we identified a centrosomal protein, c-tubulin. This association was confirmed by the reverse immunoprecipitation with c-tubulin antibodies. Both proteins copurified from HeLa cells nuclear extracts following a tandem affinity purification of double-tagged Rad51. Immunofluorescence analysis showed colocalization of both Rad51 and c-tubulin in discrete foci in mammalian cell nuclei. The number of colocalized foci and their overlapping area increased in the presence of DNA damage produced by genotoxic treatments either during S phase or in exponentially growing cells. These variations did not result from an overall stress because microtubule cytoskeleton poisons devoid of direct interactions with DNA, such as taxol or colcemid, did not lead to an increase of this association. The recruitment of Rad51 and c-tubulin in the same nuclear complex suggests a link between DNA recombination repair and the centrosome function during the cell cycle.

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“…S2A). Rad51, a recombinase that drives the HR process and recruits and forms foci at the DNA DSB sites, is an established specific cellular marker for HR activity (39,40). In addition, PARP inhibition induces Rad51 recruitment and foci formation, reflecting an increased assembly of HR repair complexes to repair persistent DNA lesions (41).…”

Section: Mrn Disruption Affects Hr and In Combination With Parpi Leamentioning

confidence: 99%

Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

Lajud

Nagda

Yamashita

et al. 2014

Clinical Cancer Research

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Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).Experimental Design: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers. Clin Cancer Res; 20(24); 6465-78. Ó2014 AACR.

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The RAD51 protein supports homologous recombination by an exchange mechanism in mammalian cells 1 1Edited by J. Karn

Cited by 63 publications

References 47 publications

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

DNA damage induce γ-tubulin–RAD51 nuclear complexes in mammalian cells

Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

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