Open AccessSCF β‐Tr CP ubiquitinates CHK 1 in an AMPK ‐dependent manner in response to glucose deprivation
Author(s) -
Ma Ying,
Cui Danrui,
Xiong Xiufang,
Inuzuka Hiroyuki,
Wei Wenyi,
Sun Yi,
North Brian J.,
Zhao Yongchao
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12403
Subject(s) - ubiquitin ligase , ampk , dna damage , effector , ubiquitin , microbiology and biotechnology , chemistry , biology , biochemistry , kinase , protein kinase a , dna , gene
The ATR / CHK 1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR / CHK 1 pathway is often inactivated by mutations, CHK 1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK 1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK 1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK 1 is ubiquitinated and degraded upon glucose deprivation by the Skp1‐Cullin‐F‐box (β‐Tr CP ) E3 ubiquitin ligase. Specifically, CHK 1 contains a β‐Tr CP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β‐Tr CP to recognize CHK 1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK 1 degradation.