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论文题目: Subcellular distribution of RAD23B controls XPC degradation and DNA damage repair in response to chemotherapy drugs
英文论文题目: Subcellular distribution of RAD23B controls XPC degradation and DNA damage repair in response to chemotherapy drugs
第一作者: You, X; Guo, WW; Wang, L; Hou, YF; Zhang, HH; Pan, Y; Han, RM; Huang, MQ; Liao, LJ; Chen, Y
英文第一作者: You, X; Guo, WW; Wang, L; Hou, YF; Zhang, HH; Pan, Y; Han, RM; Huang, MQ; Liao, LJ; Chen, Y
联系作者: Chen, Y (reprint author), Chinese Acad Sci, CAS Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci,Univ Chinese Acad Sci, Shanghai 200031, Peoples R China.
英文联系作者: Chen, Y (reprint author), Chinese Acad Sci, CAS Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci,Univ Chinese Acad Sci, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 36
期:
页码: 108-116
摘要: The RAD23B-XPC complex in the nucleus plays a key role in the initial damage recognition during global genome nucleotide excision repair (NER). Within the complex, XPC, a product of Xeroderma pigmentosum C, recognizes and interacts with the unpaired bases in the undamaged DNA strand, while RAD23B stabilizes XPC. However, how RAD23B is regulated by other factors is not well known. We report here a mode of spatial regulation of RAD23B that controls XPC stability and DNA damage repair. We first identified that RAD23B was able to directly associate with PAQR3, a newly-discovered tumor suppressor implicated in many types of human cancers. PAQR3 reduced the protein level of XPC, together with accelerated degradation and enhanced polyubiquitination of XPC. Mechanistically, PAQR3 reduces nucleic distribution of RAD23B by tethering it to the Golgi apparatus, thus diminishing the amount of RAD23B proteins available to interact with XPC in the nucleus. The viability of gastric cancer cells upon treatment with chemotherapy drugs including etoposide, cisplatin and doxorubicin was reduced by PAQR3 overexpression, but enhanced by PAQR3 knockdown. The degree of DNA damage induced by these drugs, as measured by immunoblotting with gamma-H2AX, was elevated by PAQR3 overexpression and lessened by PAQR3 knockdown. Furthermore, a synthetic peptide comprising the N-terminus of PAQR3 was able to recapitulate the activity of PAQR3 in reducing XPC stability and enhancing chemotherapy drug-induced DNA damage. In conclusion, our study reveals that RAD23B is controlled by subcellular compartmentation, thus affecting XPC-mediated DNA damage repair in cancer cells.
英文摘要: The RAD23B-XPC complex in the nucleus plays a key role in the initial damage recognition during global genome nucleotide excision repair (NER). Within the complex, XPC, a product of Xeroderma pigmentosum C, recognizes and interacts with the unpaired bases in the undamaged DNA strand, while RAD23B stabilizes XPC. However, how RAD23B is regulated by other factors is not well known. We report here a mode of spatial regulation of RAD23B that controls XPC stability and DNA damage repair. We first identified that RAD23B was able to directly associate with PAQR3, a newly-discovered tumor suppressor implicated in many types of human cancers. PAQR3 reduced the protein level of XPC, together with accelerated degradation and enhanced polyubiquitination of XPC. Mechanistically, PAQR3 reduces nucleic distribution of RAD23B by tethering it to the Golgi apparatus, thus diminishing the amount of RAD23B proteins available to interact with XPC in the nucleus. The viability of gastric cancer cells upon treatment with chemotherapy drugs including etoposide, cisplatin and doxorubicin was reduced by PAQR3 overexpression, but enhanced by PAQR3 knockdown. The degree of DNA damage induced by these drugs, as measured by immunoblotting with gamma-H2AX, was elevated by PAQR3 overexpression and lessened by PAQR3 knockdown. Furthermore, a synthetic peptide comprising the N-terminus of PAQR3 was able to recapitulate the activity of PAQR3 in reducing XPC stability and enhancing chemotherapy drug-induced DNA damage. In conclusion, our study reveals that RAD23B is controlled by subcellular compartmentation, thus affecting XPC-mediated DNA damage repair in cancer cells.
刊物名称: CELLULAR SIGNALLING
英文刊物名称: CELLULAR SIGNALLING
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学科: Cell Biology
英文学科: Cell Biology
影响因子: 3.937
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论文类别: Article
英文论文类别: Article
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