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NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies

Hyo Jei Claudia Choi1, Jia-Ren Lin, Jean-Baptiste Vannier

  • 1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94025, USA.

Molecular Cell
|August 27, 2013
PubMed

Insights

NEK8 kinase is crucial for kidney health, preventing DNA damage and kidney failure in renal ciliopathies. Loss of NEK8 function leads to DNA breaks and kidney cyst development.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Renal ciliopathies cause kidney failure, with unclear causes.
  • NEK8/NPHP9 kinase links to nephronophthisis and polycystic kidney disease.

Purpose of the Study:

  • Investigate NEK8's role in the DNA damage response.
  • Connect NEK8 function to renal ciliopathy pathogenesis.

Main Methods:

  • Studied NEK8-deficient cells and NEK8 mutant mice.
  • Analyzed DNA double-strand breaks (DSBs) and replication fork dynamics.
  • Utilized 3D kidney cell culture models.

Main Results:

  • NEK8-deficient cells accumulate spontaneous DSBs and replication stress.
  • NEK8 limits cyclin A-associated CDK activity to suppress DSBs.
  • A disease-associated NEK8 mutation impairs genome maintenance.
  • NEK8 loss or replication stress disrupts kidney cell structure.

Conclusions:

  • NEK8 is a key DNA damage response protein.
  • NEK8 links replication stress to cystic kidney disorders.
  • NEK8's genome maintenance role is vital for preventing kidney disease.

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