Defective resolution of pH2AX foci and enhanced DNA breakage in ionizing radiation‐treated cockayne syndrome B cells

Ropolo, Monica; Cappelli, Enrico; Foresta, Mara; Poggi, Alessandro; Proietti-De-Santis, Luca; Fròsina, Guido

doi:10.1002/iub.445

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…We have found that Cav-1 expression increased with time in multiple PC cell lines after radiation, similar to a previous report13. After radiation, phosphorylated H2A.X is recruited to sites of double strand DNA breaks, and itself recruits proteins to effect DNA repair3839. We have extended our results to show that Cav-1 down-regulation leads to delayed repair of radiation-induced DNA damage, as demonstrated by delayed pH2A.X foci resolution.…”

Section: Discussionsupporting

confidence: 89%

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

Chatterjee

Ben‐Josef

Thomas

et al. 2015

Sci Rep

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Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae, and has been implicated in oncogenic cell transformation, tumorigenesis, and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy, and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models, and patient samples, and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation, and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models, and human pancreatic tumors, and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation, and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo, Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK, and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo), is responsible for promoting resistance to therapies, and may serve as a prognostic/predictive biomarker and target in PC.

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Section: Discussionsupporting

confidence: 89%

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

Chatterjee

Ben‐Josef

Thomas

et al. 2015

Sci Rep

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“…The sensitivity of CSB-defective cells to oxidative DNA damage (10,11) indicates that CSB deficiency is phenotypically distinct from classic NER deficiencies and indicates that CSB function is not limited to monoadduct lesions. Therefore, transcription blockage by DSBs may also elicit CSB function to recruit repair factors most suitable for strand break repair at actively transcribed regions.…”

Section: Csb Function Is Necessary For the Recruitment Of Recombinatimentioning

confidence: 99%

“…As noted, in addition to UV sensitivity, CS patients also manifest severe neurodegeneration (8,9), suggesting the importance of CS proteins in maintaining genome stability against a broad spectrum of DNA damage. For example, CSB-defective cells are also sensitive to ionizing radiation (IR) (10,11), which is phenotypically distinctive from classic NER deficiencies and indicates that CSB function is not limited to UV-derived photo lesions. In addition, CSB-deficient mice exhibit a subset of symptoms found in patients, primarily UVC sensitivity and susceptibility to skin cancer (12).…”

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confidence: 99%

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

Wei

Nakajima

Böhm

et al. 2015

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

132

138

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Damage repair mechanisms at transcriptionally active sites during the G0/G1 phase are largely unknown. To elucidate these mechanisms, we introduced genome site-specific oxidative DNA damage and determined the role of transcription in repair factor assembly. We find that KU and NBS1 are recruited to damage sites independent of transcription. However, assembly of RPA1, RAD51C, RAD51, and RAD52 at such sites is strictly governed by active transcription and requires both wild-type Cockayne syndrome protein B (CSB) function and the presence of RNA in the G0/G1 phase. We show that the ATPase activity of CSB is indispensable for loading and binding of the recombination factors. CSB counters radiation-induced DNA damage in both cells and zebrafish models. Taken together, our results have uncovered a novel, RNA-based recombination mechanism by which CSB protects genome stability from strand breaks at transcriptionally active sites and may provide insight into the clinical manifestations of Cockayne syndrome.NA double strand breaks (DSBs) are a most severe type of DNA damage caused by endogenous metabolic processes and exogenous exposure to radiation and chemicals. Unrepaired DSBs induce genomic instability, carcinogenesis, and premature aging. In mammalian cells, DSBs are repaired by either the nonhomologous end joining (NHEJ) or the homologous recombination (HR) pathway. Although it is a common understanding that HR primarily takes place in response to strand breaks in the S-G2 phases of the cell cycle where the undamaged sister chromatids are present as donor templates, recent studies have suggested that homologous pairing also occurs during the G0/G1 phase and is associated with transcription (1), although the mechanisms remain to be elucidated. At active transcription sites, RNA polymerase II (RNA POLII) can bypass base modifications such as 8-oxo guanine but not single strand breaks (SSBs) and DSBs (2-5), indicating that unrepaired strand breaks at transcriptionally active (TA) sites can be especially deleterious and may lead to secondary damage.The Cockayne syndrome B (CSB) gene is defective in approximately two-thirds of patients with Cockayne syndrome (CS), an autosomal recessive disease with diverse clinical signs including severe growth failure, progressive neurodegeneration, and hypersensitivity to sunlight. CSB has an established role in transcription-coupled nucleotide excision repair (TC-NER) of photo lesions. When RNA POLII is stalled at bulky lesions, CSB is loaded to facilitate NER of the transcribed strand (6, 7). As noted, in addition to UV sensitivity, CS patients also manifest severe neurodegeneration (8, 9), suggesting the importance of CS proteins in maintaining genome stability against a broad spectrum of DNA damage. For example, CSB-defective cells are also sensitive to ionizing radiation (IR) (10, 11), which is phenotypically distinctive from classic NER deficiencies and indicates that CSB function is not limited to UV-derived photo lesions. In addition, CSB-deficient mice exhibit a subset of sy...

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Transcription-coupled homologous recombination after oxidative damage

2016

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Defective resolution of pH2AX foci and enhanced DNA breakage in ionizing radiation‐treated cockayne syndrome B cells

Cited by 4 publications

References 19 publications

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

Transcription-coupled homologous recombination after oxidative damage

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