Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage
In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be eluci...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2017-07-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317712102 |
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| author | Haiyang Yu Xiaoqing Zhang Ren Liu Hui Li Xiaolong Xiao Yuzheng Zhou Chaoying Wei Manyi Yang Mingmei Liao Jinfeng Zhao Zanxian Xia Qiande Liao |
| author_facet | Haiyang Yu Xiaoqing Zhang Ren Liu Hui Li Xiaolong Xiao Yuzheng Zhou Chaoying Wei Manyi Yang Mingmei Liao Jinfeng Zhao Zanxian Xia Qiande Liao |
| author_sort | Haiyang Yu |
| collection | DOAJ |
| description | In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid–induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1 ). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis. |
| format | Article |
| id | doaj-art-dee95905edbd4d1e9a968ec546e875eb |
| institution | Kabale University |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Tumor Biology |
| spelling | doaj-art-dee95905edbd4d1e9a968ec546e875eb2025-08-20T03:38:50ZengSAGE PublishingTumor Biology1423-03802017-07-013910.1177/1010428317712102Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damageHaiyang Yu0Xiaoqing Zhang1Ren Liu2Hui Li3Xiaolong Xiao4Yuzheng Zhou5Chaoying Wei6Manyi Yang7Mingmei Liao8Jinfeng Zhao9Zanxian Xia10Qiande Liao11Xiangya Hospital, Central South University, Changsha, P.R. ChinaThe Fifth Xiangya Hospital, Central South University, Changsha, P.R. ChinaMerck Research Laboratory, Kenilworth, NJ, USAState Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, P.R. ChinaState Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, P.R. ChinaState Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, P.R. ChinaState Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, P.R. ChinaXiangya Hospital, Central South University, Changsha, P.R. ChinaXiangya Hospital, Central South University, Changsha, P.R. ChinaXiangya Hospital, Central South University, Changsha, P.R. ChinaState Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, P.R. ChinaXiangya Hospital, Central South University, Changsha, P.R. ChinaIn cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid–induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1 ). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.https://doi.org/10.1177/1010428317712102 |
| spellingShingle | Haiyang Yu Xiaoqing Zhang Ren Liu Hui Li Xiaolong Xiao Yuzheng Zhou Chaoying Wei Manyi Yang Mingmei Liao Jinfeng Zhao Zanxian Xia Qiande Liao Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage Tumor Biology |
| title | Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage |
| title_full | Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage |
| title_fullStr | Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage |
| title_full_unstemmed | Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage |
| title_short | Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage |
| title_sort | mcl 1 suppresses abasic site repair following bile acid induced hepatic cellular dna damage |
| url | https://doi.org/10.1177/1010428317712102 |
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