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

N Kanu1, T Zhang1, R A Burrell2

  • 1Mammalian Genetics Laboratory, The Francis Crick Institute, London, UK.

Oncogene
|November 10, 2015
PubMed

Insights

Replication stress activates ATM signaling through monoubiquitinated PCNA, a stalled replication fork marker. WRNIP1 bridges this interaction, ensuring genomic stability by activating ATM signaling pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA replication encounters obstacles, causing replication stress.
  • Replication stress activates ATR and ATM kinases, crucial for DNA repair and genomic stability.
  • The mechanism of ATM activation by replication stress is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism of ATM activation in response to replication stress.
  • To identify the key proteins involved in linking stalled replication forks to ATM signaling.

Main Methods:

  • Investigated the interaction between monoubiquitinated PCNA and ATM cofactors.
  • Utilized WRNIP1 and RAD18 in replication stress models.
  • Assessed ATM signaling and 53BP1 focus formation.

Main Results:

  • Monoubiquitinated PCNA interacts with ATM cofactor ATMIN via WRNIP1.
  • ATMIN, WRNIP1, and RAD18 are essential for ATM signaling and 53BP1 focus formation induced by replication stress.
  • This pathway is distinct from ATM activation by ionizing radiation.

Conclusions:

  • WRNIP1 acts as a crucial link between PCNA monoubiquitination and ATMIN/ATM activation.
  • This mechanism is vital for activating ATM signaling during replication stress.
  • The findings contribute to understanding genomic stability maintenance.

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