RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress

Oncogene. 2016 Jul 28;35(30):4009-19. doi: 10.1038/onc.2015.427. Epub 2015 Nov 9.


The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here, we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN-interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Aphidicolin / pharmacology
  • Ataxia Telangiectasia Mutated Proteins / physiology*
  • Carrier Proteins / physiology*
  • DNA Damage
  • DNA Replication*
  • DNA-Binding Proteins / physiology*
  • Genomic Instability
  • Humans
  • Proliferating Cell Nuclear Antigen / metabolism
  • Signal Transduction / physiology*
  • Transcription Factors / physiology*
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitination


  • ATMIN protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Proliferating Cell Nuclear Antigen
  • RAD18 protein, human
  • Transcription Factors
  • Aphidicolin
  • Ubiquitin-Protein Ligases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • WRNIP1 protein, human
  • ATPases Associated with Diverse Cellular Activities