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

Mol Cell. 2013 Aug 22;51(4):423-39. doi: 10.1016/j.molcel.2013.08.006.

Abstract

Renal ciliopathies are a leading cause of kidney failure, but their exact etiology is poorly understood. NEK8/NPHP9 is a ciliary kinase associated with two renal ciliopathies in humans and mice, nephronophthisis (NPHP) and polycystic kidney disease. Here, we identify NEK8 as a key effector of the ATR-mediated replication stress response. Cells lacking NEK8 form spontaneous DNA double-strand breaks (DSBs) that further accumulate when replication forks stall, and they exhibit reduced fork rates, unscheduled origin firing, and increased replication fork collapse. NEK8 suppresses DSB formation by limiting cyclin A-associated CDK activity. Strikingly, a mutation in NEK8 that is associated with renal ciliopathies affects its genome maintenance functions. Moreover, kidneys of NEK8 mutant mice accumulate DNA damage, and loss of NEK8 or replication stress similarly disrupts renal cell architecture in a 3D-culture system. Thus, NEK8 is a critical component of the DNA damage response that links replication stress with cystic kidney disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Culture Techniques
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cilia / metabolism
  • Cilia / pathology*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • DNA Damage / genetics
  • DNA Replication / genetics*
  • Genomic Instability
  • Humans
  • Mice
  • Mutation / genetics
  • NIMA-Related Kinases
  • Phosphorylation
  • Polycystic Kidney Diseases / metabolism
  • Polycystic Kidney Diseases / pathology*
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • S Phase / physiology*
  • Stress, Physiological

Substances

  • Cell Cycle Proteins
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • NEK8 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinases