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BMC Molecular Biology (1)
Drug Design, Development and Therapy (1)
Nucleic Acids Research (1)
Chen, Benjamin PC (3)
Cheng, Yi (1)
Guerra, Barbara (1)
Li, Mengxia (1)
Lin, Yu-Fen (1)
Matsunaga, Shinji (1)
Olsen, Birgitte B (1)
Qian, Chengyuan (1)
Shang, Zengfu (1)
Shih, Hung-Ying (1)
Sui, Jiangdong (1)
Svenstrup, Tina H (1)
Wang, Dong (1)
Wang, Shih-Ya (1)
Wang, Shufeng (1)
Year of Publication
Functional analysis of tanshinone IIA that blocks the redox function of human apurinic/apyrimidinic endonuclease 1/redox factor-1
Drug Design, Development and Therapy
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein possessing both DNA repair and redox regulatory activities. It has been shown that blocking redox function leads to genotoxic, antiangiogenic, cytostatic, and proapoptotic effects in cells. Therefore, the selective inhibitors against APE1’s redox function can be served as potential pharmaceutical candidates in cancer therapeutics. In the present study, we identified the biological specificity of the Chinese herbal compound tanshinone IIA (T2A) in blocking the redox function of APE1. Using dual polarization interferometry, the direct interaction between APE1 and T2A was observed with a KD value at subnanomolar level. In addition, we showed that T2A significantly compromised the growth of human cervical cancer and colon cancer cells. Furthermore, the growth-inhibitory or proapoptotic effect of T2A was diminished in APE1 knockdown or redox-deficient cells, suggesting that the cytostatic effect of T2A might be specifically through inhibiting the redox function of APE1. Finally, T2A pretreatment enhanced the cytotoxicity of ionizing radiation or other chemotherapeutic agents in human cervical cancer and colon cancer cell lines. The data presented herein suggest T2A as a promising bioactive inhibitor of APE1 redox activity.
tanshinone IIA; APE1; redox activity; multifunctional protein
DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response
Nucleic Acids Research
The ataxia telangiectasia mutated and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis is the major signaling pathway activated in response to replication stress and is essential for the intra-S checkpoint. ATR phosphorylates and activates a number of molecules to coordinate cell cycle progression. Chk1 is the major effector downstream from ATR and plays a critical role in intra-S checkpoint on replication stress. Activation of Chk1 kinase also requires its association with Claspin, an adaptor protein essential for Chk1 protein stability, recruitment and ATR-dependent Chk1 phosphorylation. We have previously reported that, on replication stress, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is rapidly phosphorylated by ATR at the stalled replication forks and is required for cellular resistance to replication stresses although the impact of DNA-PKcs onto the ATR signaling pathway remains elusive. Here we report that ATR-dependent Chk1 phosphorylation and Chk1 signaling are compromised in the absence of DNA-PKcs. Our investigation reveals that DNA-PKcs is required to maintain Chk1–Claspin complex stability and transcriptional regulation of Claspin expression. The impaired Chk1 activity results in a defective intra-S checkpoint response in DNA-PKcs–deficient cells. Taken together, these results suggest that DNA-PKcs, in addition to its direct role in DNA damage repair, facilitates ATR-Chk1 signaling pathway in response to replication stress.
Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage
Olsen, Birgitte B
Svenstrup, Tina H
BMC Molecular Biology
The DNA-dependent protein kinase (DNA-PK) is a nuclear complex composed of a large catalytic subunit (DNA-PKcs) and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the non-homologous end-joining (NHEJ) repair mechanism, which is activated in the presence of DNA double-strand breaks induced by ionizing radiation, reactive oxygen species and radiomimetic drugs. We have recently reported that down-regulation of protein kinase CK2 by siRNA interference results in enhanced cell death specifically in DNA-PKcs-proficient human glioblastoma cells, and this event is accompanied by decreased autophosphorylation of DNA-PKcs at S2056 and delayed repair of DNA double-strand breaks.
In the present study, we show that CK2 co-localizes with phosphorylated histone H2AX to sites of DNA damage and while CK2 gene knockdown is associated with delayed DNA damage repair, its overexpression accelerates this process. We report for the first time evidence that lack of CK2 destabilizes the interaction of DNA-PKcs with DNA and with Ku80 at sites of genetic lesions. Furthermore, we show that CK2 regulates the phosphorylation levels of DNA-PKcs only in response to direct induction of DNA double-strand breaks.
Taken together, these results strongly indicate that CK2 plays a prominent role in NHEJ by facilitating and/or stabilizing the binding of DNA-PKcs and, possibly other repair proteins, to the DNA ends contributing to efficient DNA damage repair in mammalian cells.
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