Corrupting the DNA damage response: a critical role for Rad52 in tumor cell survival

Lieberman, Rachel; You, Ming

doi:10.18632/aging.101263

Cited by 12 publications

(14 citation statements)

References 85 publications

(113 reference statements)

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“…Our results are similar to those previously observed for the related DNA repair protein, RAD52, in lung cancer (8,9). RAD52 is predominantly recruited for DNA repair during the S phase of the cell cycle and plays a crucial role in the regulation of homologous recombination-related genomic instability in humans (25).…”

Section: Discussionsupporting

confidence: 91%

“…In addition to drug resistance, proteins involved in DNA repair pathways have been implicated in tumor progression (22). For example, RAD52 has been linked to both the progression and risk of small cell lung cancer (SCLC) and NSCLC (8,9,23). In addition, RDM1 was previously shown to undergo stress-induced nucleolar accumulation, indicating it may function in the heat-shock response that is implicated in tumorigenesis (16).…”

Section: Discussionmentioning

confidence: 99%

“…Components of the DNA damage response pathway have not only been implicated in chemoresistance, but they themselves may play oncogenic roles (8,9). Indeed, the capacity to repair damaged DNA through homologous recombination has previously been implicated in patient susceptibility to lung cancer (10,11).…”

Section: Introductionmentioning

confidence: 99%

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RAD52 motif‑containing protein�1 promotes non‑small cell lung cancer cell proliferation and survival via cell cycle regulation

Wang

et al. 2018

Oncol Rep

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DNA repair proteins such as RAD52 have been implicated in tumor progression and response to chemotherapy. RAD52 motif‑containing protein 1 (RDM1) has been implicated in the response to chemotherapeutic agent cisplatin; however, its function in lung cancer progression remains unclear. This study aimed to investigate the role of RDM1 in the progression of non‑small cell lung cancer (NSCLC). We found elevated RDM1 mRNA and protein expression in NSCLC tissues and cell lines compared to levels in normal lung cells. RDM1 protein expression in lung cancer tissues was found to correlate with tumor size, histological differentiation, lymph node metastasis and tumor‑node‑metastasis (TNM) stage. Knockdown of the RDM1 gene with siRNA significantly reduced the cellular proliferation rate and increased apoptosis in the human NSCLC cell line, NCI‑H1299. Compared to wild‑type NCI‑H1299 cells, RDM1 knockdown enhanced the activity of caspase‑3 and caspase‑7, and decreased the proportion of cells in the S‑phase of the cell cycle. Taken together, these data imply that RDM1 promotes the survival and proliferation of NSCLC cells. Due to its similarity to RAD52, we hypothesized that RDM1 potentially repairs DNA double‑strand breaks arising through DNA replication, thereby preventing G2/M cell cycle arrest. Accordingly, specific targeting of RDM1 may be a novel therapeutic strategy in the treatment of NSCLC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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RAD52 motif‑containing protein�1 promotes non‑small cell lung cancer cell proliferation and survival via cell cycle regulation

Wang

et al. 2018

Oncol Rep

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“…Defect in DDR related genes in tumor cells leads to impaired DNA repair, triggering apoptosis in tumor cells. Recent studies have demonstrated that DDR is important for the maintenance of tumor genome integrity, and dysregulation of DDR sensitizes tumor cells to chemotherapy [45][46][47][48]. Thus, inhibition of DDR pathway including HR and NHEJ via chemotherapeutic compounds selectively kill tumor cells that evolve to escape DDR and checkpoint signaling.…”

Section: Discussionmentioning

confidence: 99%

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

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“…Unlike normal cells, cancer cells maintain a marked level of genomic instability and will be associated with replication stress factors such as cell cycle checkpoint loss, increased transcription, higher levels of metabolic stress, increased ROS formation and activation of oncogenic drivers . The principle hallmarks of cancers are their propensity to accumulate DNA damage and their decreased traditional repair capacity, leading cancer cells to become exceedingly more dependent on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy‐induced DSBs in DNA . Therefore, DNA‐damaging regimes, such as TB, could selectively induce tumour cell apoptosis by augmenting genomic instability, and the DNA repair mechanisms would work efficiently in normal cells in contrast to tumour cells.…”

Section: Discussionmentioning

confidence: 99%

Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway

Jin

Zhou

Yan

et al. 2018

J Cellular Molecular Medi

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Osteosarcoma becomes the second leading cause of cancer death in the younger population. Current outcomes of chemotherapy on osteosarcoma were unsatisfactory to date, demanding development of effective therapies. Tea is a commonly used beverage beneficial to human health. As a major component of tea, theabrownin has been reported to possess anti‐cancer activity. To evaluate its anti‐osteosarcoma effect, we established a xenograft model of zebrafish and employed U2OS cells for in vivo and in vitro assays. The animal data showed that TB significantly inhibited the tumour growth with stronger effect than that of chemotherapy. The cellular data confirmed that TB‐triggered DNA damage and induced apoptosis of U2OS cells by regulation of Mki67, PARP, caspase 3 and H2AX, and Western blot assay showed an activation of p53 signalling pathway. When P53 was knocked down by siRNA, the subsequent downstream signalling was blocked, indicating a p53‐dependent mechanism of TB on U2OS cells (p53 wt). Using osteosarcoma cell lines with p53 mutations (HOS, SAOS‐2 and MG63), we found that TB exerted stronger inhibitory effect on U2OS cells than that on p53‐mut cell lines, but it also exerted obvious effect on SAOS‐2 cells (p53 null), suggesting an activation of p53‐independent pathway in the p53‐null cells. Interestingly, theabrownin was found to have no toxicity on normal tissue in vivo and could even increase the viability of p53‐wt normal cells. In sum, theabrownin could trigger DNA damage and induce apoptosis on U2OS cells via a p53‐dependent mechanism, being a promising candidate for osteosarcoma therapy.

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Corrupting the DNA damage response: a critical role for Rad52 in tumor cell survival

Cited by 12 publications

References 85 publications

RAD52 motif‑containing protein�1 promotes non‑small cell lung cancer cell proliferation and survival via cell cycle regulation

RAD52 motif‑containing protein�1 promotes non‑small cell lung cancer cell proliferation and survival via cell cycle regulation

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway

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