ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair

Nucleic Acids Research, Feb 2018

Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3′ or 5′ overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.

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ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair

Nucleic Acids Research ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair Guo Chen 1 2 Jianxiang Chen 0 2 6 Yiting Qiao 2 Yaru Shi 5 Wei Liu 4 5 Qi Zeng 5 Hui Xie 5 Xiaorui Shi 5 Youwei Sun 1 Xu Liu 3 Tongyu Li 2 Liqian Zhou 2 Jianqin Wan 2 Tian Xie 0 Hangxiang Wang 2 Fu Wang 5 0 Holistic Integrative Pharmacy Institutes (HIPI), Hangzhou Normal University, Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province , Hangzhou 311100 , PR China 1 Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University , Atlanta, GA 30322 , USA 2 The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003 , PR China 3 Department of Biochemistry, Emory University School of Medicine , Atlanta, GA 30322 , USA 4 Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University , Xi'an, Shaanxi 710032 , China 5 Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University , Xi'an 710071 , China 6 Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre , Singapore 169610 , Singapore Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3 or 5 overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830. - DNA double-strand breaks (DSBs) are highly toxic lesions that can be generated by a variety of exogenous sources including ionizing radiation, mutagenic chemicals and chemotherapeutic drugs ( 1 ). DSBs can also arise from endogenous oxidative stress and replication fork collapse triggered by problems encountered during DNA replication ( 2 ). Failures to correctly repair DSBs may result in propagation of mutations, chromosomal translocations, genome instability, tumorigenesis, cell senescence and death ( 3 ). Therefore, it is crucial that cells must quickly detect DSBs and get them efficient repaired. DNA DSBs are primarily repaired by two major pathways: homologous recombination (HR) and nonhomologous end-joining (NHEJ) ( 4 ). NHEJ is active in all phase of cell cycle, while HR, which requires the identical sister chromatid as the template for completing the repair, occurs preferentially in S and G2 phase ( 4–7 ). NHEJ directly ligates the broken DNA ends, usually causing small deletions and additions, thus, it is considered as error-prone repair (8). Whereas HR requires sequence-homologous template to repair and restore the broken DNA molecules, therefore, HR repair is considered as error-free process ( 4 ). NHEJ and HR repairs are executed by different machineries, respectively. NHEJ is initiated by recognition and binding of the Ku70/Ku80 heterodimer to the DNA ends, followed by the recruitment and activation of DNA-dependent protein kinase (DNA-PKcs) and the XRCC4/ligase IV complex, which joins the DNA ends together ( 9 ). During HR, DSBs is firstly recognized by MRN complex (Mre11–Rad50–NBS1) and initiated by MRN mediated DSB end resection and generating 3 single-stranded DNA (ssDNA) overhangs ( 10 ). The resulted ssDNA overhang is rapidly bound by replication protein A (RPA), which is subsequently displaced by Rad51 recombinase ( 11,12 ). Rad51 coats on ssDNA and form a nucleoprotein filament that allows strand invasion and homology search (11). During the DNA end resection, CtIP (also known as RBBP8) is recruited to the DSBs sites and interacts with MRN ( 7,13 ). CtIP promotes end resection through stimulating the nuclease activity of MRN, accelerating gen (...truncated)


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Chen, Guo, Chen, Jianxiang, Qiao, Yiting, Shi, Yaru, Liu, Wei, Zeng, Qi, Xie, Hui, Shi, Xiaorui, Sun, Youwei, Liu, Xu, Li, Tongyu, Zhou, Liqian, Wan, Jianqin, Xie, Tian, Wang, Hangxiang, Wang, Fu. ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair, Nucleic Acids Research, 2018, pp. 1266-1279, Volume 46, Issue 3, DOI: 10.1093/nar/gkx1258