Kanu, N;
Zhang, T;
Burrell, RA;
Chakraborty, A;
Cronshaw, J;
DaCosta, C;
Grönroos, E;
... Behrens, A; + view all
(2015)
RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress.
Oncogene
, 35
(30)
pp. 4009-4019.
10.1038/onc.2015.427.
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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.
| Type: | Article |
|---|---|
| Title: | RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/onc.2015.427 |
| Publisher version: | https://doi.org/10.1038/onc.2015.427 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Oncology, Cell Biology, Genetics & Heredity, DOUBLE-STRAND BREAKS, CELL NUCLEAR ANTIGEN, DNA-DAMAGE, MONOUBIQUITINATED PCNA, ANAPHASE BRIDGES, MAMMALIAN-CELLS, FOCUS FORMATION, ACTIVATION, FORKS, CHECKPOINT |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205415 |
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