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Targeting RAD51 enhances chemosensitivity of adult T?cell leukemia?lymphoma cells by reducing DNA double?strand break repair.

ABSTRACT: RAD51, is a key homologous recombination protein that repairs DNA damage and maintains gene diversity and stability. Previous studies have demonstrated that the over?expression of RAD51 is associated with chemotherapy resistance of tumor cells to chemotherapy, and enhanced activity of DNA damage repair (DDR) systems contributes to resistance of adult T?cell leukemia?lymphoma (ATL) resistance to chemotherapy. Thus, targeting RAD51 is a potential strategy for the sensitization of ATL cells to chemotherapeutic drugs by inducing DNA damage. In general, cells can repair minor DNA damage through DDR; however, serious DNA damage may cause cell toxicity in cells which cannot be restored. In the present, down regulation of RAD51 by shRNA and imatinib sensitized Jurkat cells to etoposide by decreasing the activity of homologous recombination (HR). We found that the suppression of RAD51 by shRNA inhibited tumor cells proliferation and enhanced apoptosis of Jurkat cells after etoposide treatment. Importantly, downregulation of RAD51 by imatinib obviously increased the apoptosis of Jurkat cell after etoposide treatment. These results demonstrated that RAD51 may be of great value to as a novel target for the clinical treatment of adult T?cell leukemia?lymphoma (ATL), and it may improve the survival of leukemia patients.

SUBMITTER: Yang M

PROVIDER: S-EPMC6859462 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Targeting RAD51 enhances chemosensitivity of adult T‑cell leukemia‑lymphoma cells by reducing DNA double‑strand break repair.

Yang Meng M Tian Xiaoxue X Fan Zhuoyi Z Yu Wenlei W Li Zheng Z Zhou Jie J Zhang Wenjun W Liang Aibin A

Oncology reports 20191022 6

RAD51, is a key homologous recombination protein that repairs DNA damage and maintains gene diversity and stability. Previous studies have demonstrated that the over‑expression of RAD51 is associated with chemotherapy resistance of tumor cells to chemotherapy, and enhanced activity of DNA damage repair (DDR) systems contributes to resistance of adult T‑cell leukemia‑lymphoma (ATL) resistance to chemotherapy. Thus, targeting RAD51 is a potential strategy for the sensitization of ATL cells to chem ...[more]

PMID: 31638261

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Project description:Expression of RAD51, a crucial player in homologous recombination (HR) and DNA double-strand break (DSB) repair, is dysregulated in human tumors, and can contribute to genomic instability and tumor progression. To further understand RAD51 regulation we functionally characterized a long non-coding (lnc) RNA, dubbed TODRA (Transcribed in the Opposite Direction of RAD51), transcribed 69bp upstream to RAD51, in the opposite direction. We demonstrate that TODRA is an expressed transcript and that the RAD51 promoter region is bidirectional, supporting TODRA expression (7-fold higher than RAD51 in this assay, p = 0.003). TODRA overexpression in HeLa cells induced expression of TPIP, a member of the TPTE family which includes PTEN. Similar to PTEN, we found that TPIP co-activates E2F1 induction of RAD51. Analysis of E2F1's effect on the bidirectional promoter showed that E2F1 binding to the same site that promotes RAD51 expression, results in downregulation of TODRA. Moreover, TODRA overexpression induces HR in a RAD51-dependent DSB repair assay, and increases formation of DNA damage-induced RAD51-positive foci. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates RAD51 and TODRA: increased RAD51 expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and HER2 amplification (r = 0.41, p = 0.001)), correlates as expected with lower TODRA and higher E2F1 expression. However, although E2F1 induction resulted in TPIP downregulation in cell lines, we find that TPIP expression in tumors is not reduced despite higher E2F1 expression, perhaps contributing to increased RAD51 expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the TODRA lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates RAD51 and TODRA: increased RAD51 expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and HER2 amplification (r = 0.41, p = 0.001)), correlates as expected with lower TODRA and higher E2F1 expression. However, although E2F1 induction resulted in TPIP downregulation in cell lines, we find that TPIP expression in tumors is not reduced despite higher E2F1 expression, perhaps contributing to increased RAD51 expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the TODRA lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy.

Dataset Information

Targeting RAD51 enhances chemosensitivity of adult T?cell leukemia?lymphoma cells by reducing DNA double?strand break repair.

Publications

Targeting RAD51 enhances chemosensitivity of adult T‑cell leukemia‑lymphoma cells by reducing DNA double‑strand break repair.

Similar Datasets

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