The ATM kinase induces microRNA biogenesis in the DNA damage response

Mol Cell. 2011 Feb 18;41(4):371-83. doi: 10.1016/j.molcel.2011.01.020.

Abstract

The DNA damage response involves a complex network of processes that detect and repair DNA damage. Here we show that miRNA biogenesis is globally induced upon DNA damage in an ATM-dependent manner. About one-fourth of miRNAs are significantly upregulated after DNA damage, while loss of ATM abolishes their induction. KH-type splicing regulatory protein (KSRP) is a key player that translates DNA damage signaling to miRNA biogenesis. The ATM kinase directly binds to and phosphorylates KSRP, leading to enhanced interaction between KSRP and pri-miRNAs and increased KSRP activity in miRNA processing. Mutations of the ATM phosphorylation sites of KSRP impaired its activity in regulating miRNAs. These findings reveal a mechanism by which DNA damage signaling is linked to miRNA biogenesis.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • DNA Damage / physiology*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Mice
  • MicroRNAs / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • KHSRP protein, human
  • KSRP protein, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • Trans-Activators
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases