SCFβ-TrCP ubiquitinates CHK1 in an AMPK-dependent manner in response to glucose deprivation

Mol Oncol. 2019 Feb;13(2):307-321. doi: 10.1002/1878-0261.12403. Epub 2018 Dec 3.

Abstract

The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 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 CHK1 degradation through the ubiquitin-proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (β-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β-TrCP to recognize CHK1 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 CHK1 degradation.

Keywords: AMPK; CHK1; glucose deprivation; ubiquitination; β-TrCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Amino Acid Sequence
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Checkpoint Kinase 1 / metabolism*
  • Enzyme Stability / drug effects
  • Glucose / deficiency*
  • HEK293 Cells
  • Humans
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Domains
  • Proteolysis / drug effects
  • Staurosporine / pharmacology
  • Ubiquitination* / drug effects
  • beta-Transducin Repeat-Containing Proteins / chemistry
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • beta-Transducin Repeat-Containing Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • AMP-Activated Protein Kinases
  • Staurosporine
  • Glucose