NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint

Nat Cell Biol. 2009 Oct;11(10):1247-53. doi: 10.1038/ncb1969. Epub 2009 Sep 6.


DNA damage-induced cell-cycle checkpoints have a critical role in maintaining genomic stability. A key target of the checkpoints is the CDC25A (cell division cycle 25 homologue A) phosphatase, which is essential for the activation of cyclin-dependent kinases and cell-cycle progression. To identify new genes involved in the G2/M checkpoint we performed a large-scale short hairpin RNA (shRNA) library screen. We show that NIMA (never in mitosis gene A)-related kinase 11 (NEK11) is required for DNA damage-induced G2/M arrest. Depletion of NEK11 prevents proteasome-dependent degradation of CDC25A, both in unperturbed and DNA-damaged cells. We show that NEK11 directly phosphorylates CDC25A on residues whose phosphorylation is required for beta-TrCP (beta-transducin repeat-containing protein)-mediated polyubiquitylation and degradation of CDC25A. Furthermore, we demonstrate that CHK1 (checkpoint kinase 1) directly activates NEK11 by phosphorylating it on Ser 273, indicating that CHK1 and NEK11 operate in a single pathway that controls proteolysis of CDC25A. Taken together, these results demonstrate that NEK11 is an important component of the pathway enforcing the G2/M checkpoint, suggesting that genetic mutations in NEK11 may contribute to the development of human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Checkpoint Kinase 1
  • Enzyme Activation
  • G2 Phase / genetics
  • G2 Phase / radiation effects*
  • HeLa Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mitosis
  • Molecular Sequence Data
  • NIMA-Related Kinases
  • Phosphorylation
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • RNA, Small Interfering / metabolism
  • Radiation, Ionizing
  • Recombinant Proteins / metabolism
  • Serine / metabolism
  • Transfection
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism
  • cdc25 Phosphatases / chemistry
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism*


  • RNA, Small Interfering
  • Recombinant Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Serine
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • NIMA-Related Kinases
  • Nek11 protein, human
  • cdc25 Phosphatases