2. Academic Validation
  3. Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates

Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates

  • Cell Death Differ. 2024 Nov 27. doi: 10.1038/s41418-024-01422-2.
Jing Yang 1,  Shi-Yuan Wan 1,  Qiu-Yi Song 1,  Yun-Hao Xie 2,  Jun Wan 2,  Yi-Hao Zhou 2,  Zi-Tong Zhang 1,  Yu-Shuo Xiao 1,  Xi Li 1,  Hong Chen 1,  Xin-Ran Liu 1,  Li Xu 1,  Hui-Juan You 1,  De-Sheng Hu 3 4,  Robert B Petersen 5,  Yong-Hui Zhang 1,  Ling Zheng 2,  Yu Zhang 6,  Kun Huang 7 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 3 Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 4 China-Russia Medical Research Center for Stress Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 5 Foundational Sciences, Central Michigan University College of Medicine, Mt. Pleasant, MI, 48858, USA.
  • 6 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China. yuzhang@hust.edu.cn.
  • 7 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China. kunhuang@hust.edu.cn.
  • 8 Tongji-Rong Cheng Biomedical Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. kunhuang@hust.edu.cn.
PMID: 39592710 DOI: 10.1038/s41418-024-01422-2
Abstract

Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or Apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards Apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and Apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal Apoptosis to safeguard genome integrity.

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