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Lookup NU author(s): Dr Jill Hunter, Dr Nicola Hannaway, Scott Kerridge, Dr Saimir LuliORCiD, Dr Jacqueline Butterworth, Helene Sellier, Reshmi Mukherjee, Nikita Dhillon, Dr Ruchi ShuklaORCiD, Dr Hayden BellORCiD, Dr Jonathan Coxhead, Leigh Taylor, Dr Peter Leary, Dr Megan Hasoon, Professor Neil PerkinsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel-/- lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.
Author(s): Hunter JE, Campbell AE, Hannaway NL, Kerridge S, Luli S, Butterworth JA, Sellier H, Mukherjee R, Dhillon N, Sudhindar PD, Shukla R, Brownridge PJ, Bell HL, Coxhead J, Taylor L, Leary P, Hasoon MSR, Collins I, Garrett MD, Eyers CE, Perkins ND
Publication type: Article
Publication status: Published
Journal: Biochemical Journal
Year: 2022
Volume: 479
Issue: 19
Pages: 2063-2086
Print publication date: 01/10/2022
Online publication date: 24/08/2022
Acceptance date: 23/08/2022
Date deposited: 02/11/2022
ISSN (print): 0264-6021
ISSN (electronic): 1470-8728
Publisher: Portland Press
URL: https://doi.org/10.1042/BCJ20220102
DOI: 10.1042/BCJ20220102
PubMed id: 36240066
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