Hunter, Jill E, Campbell, Amy E, Butterworth, Jacqueline A, Sellier, Helene, Hannaway, Nicola L, Luli, Saimir, Floudas, Achilleas, Kenneth, Niall S 
ORCID: 0000-0001-8528-1021, Moore, Adam J, Brownridge, Philip J et al (show 10 more authors)
(2022)
Mutation of the RelA(p65) Thr505 phosphosite disrupts the DNA replication stress response leading to CHK1 inhibitor resistance.
BIOCHEMICAL JOURNAL, 479 (19).
pp. 2087-2113.
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Abstract
DNA replication stress resulting from the activity of oncogenes such as MYC, is a common feature of cancer cells. To cope with this challenge, tumours become addicted to ATR/CHK1 signalling, thus making these kinases attractive targets for anti-cancer therapies. Here, we demonstrate that the RelA (p65) NF-κB subunit is an important regulator of MYC induced DNA replication stress in vivo. Using the Eμ-Myc model of B-cell lymphoma, mice mutated at the putative CHK1 T505 phosphosite (T505A) in the RelA transactivation domain, exhibited reduced survival. Moreover, and in contrast with wild-type (WT) Eμ-Myc lymphomas, RelA T505A Eμ-Myc lymphomas are resistant to treatment with the CHK1 inhibitor CCT244747. Total protein and phosphopeptide proteomic analysis revealed that the response of RelA T505A Eμ-Myc lymphomas to a single acute dose of CCT244747 in vivo, was both reduced and different from WT cells. Subsequent examination of ATR/CHK1 signalling components revealed loss of expression of the ATR/CHK1 adaptor protein Claspin in RelA T505A Eμ-Myc lymphomas. Taken together our data reveal a critical role for RelA as a regulator of the DNA replication stress in vivo. We propose that by maintaining high Claspin levels, phosphorylation of the T505 site by CHK1 is required for efficient activation of CHK1 by ATR, thus driving the reliance on signalling through the ATR/CHK1 pathway required to survive high levels of DNA replication stress in cancer cells.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Protein Kinase Inhibitors, DNA Replication, Mutation |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 21 Oct 2022 08:33 |
| Last Modified: | 18 Jan 2023 19:49 |
| DOI: | 10.1042/BCJ20220089 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165685 |
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