Details

Autor(en) / Beteiligte

• Chen, Yuping
• Wu, Jinhuan
• Liang, Guang
• Geng, Guohe
• Zhao, Fei
• Yin, Ping
• Nowsheen, Somaira
• Wu, Chengming
• Li, Yunhui
• Li, Lei
• Kim, Wootae
• Zhou, Qin
• Huang, Jinzhou
• Liu, Jiaqi
• Zhang, Chao
• Guo, Guijie
• Deng, Min
• Tu, Xinyi
• Gao, Xiumei
• Liu, Zhongmin
• Chen, Yihan
• Lou, Zhenkun
• Luo, Kuntian
• Yuan, Jian

Titel

CHK2-FOXK axis promotes transcriptional control of autophagy programs

Ist Teil von

• Science advances, 2020-01, Vol.6 (1), p.eaax5819-eaax5819

Ort / Verlag

United States: American Association for the Advancement of Science

Erscheinungsjahr

2020

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Autophagy is an evolutionarily conserved catabolic process, which plays a vital role in removing misfolded proteins and clearing damaged organelles to maintain internal environment homeostasis. Here, we uncovered the checkpoint kinase 2 (CHK2)-FOXK (FOXK1 and FOXK2) axis playing an important role in DNA damage-mediated autophagy at the transcriptional regulation layer. Mechanistically, following DNA damage, CHK2 phosphorylates FOXK and creates a 14-3-3γ binding site, which, in turn, traps FOXK proteins in the cytoplasm. Because FOXK functions as the transcription suppressor of ATGs, DNA damage-mediated FOXKs' cytoplasmic trapping induces autophagy. In addition, we found that a cancer-derived FOXK mutation induces FOXK hyperphosphorylation and enhances autophagy, resulting in chemoresistance. Cotreatment with cisplatin and chloroquine overcomes the chemoresistance caused by FOXK mutation. Overall, our study highlights a mechanism whereby DNA damage triggers autophagy by increasing autophagy genes via CHK2-FOXK-mediated transcriptional control, and misregulation of this pathway contributes to chemoresistance.