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

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

Author information

1
Mammalian Genetics Laboratory, The Francis Crick Institute, London, UK.
2
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
3
Molecular Oncology Laboratory, The Francis Crick Institute, London, UK.
4
DNA Damage Tolerance Laboratory, The Francis Crick Institute, London, UK.
5
Istituto di Genetica Molecolare-CNR, Pavia, Italy.
6
UCL Cancer Institute, London, UK.
7
School of Medicine, King's College London, Guy's Campus, London, UK.

Abstract

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.

PMID:
26549024
PMCID:
PMC4842010
DOI:
10.1038/onc.2015.427
[Indexed for MEDLINE]
Free PMC Article

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