Toggle Main Menu Toggle Search

Open Access padlockePrints

Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway

Lookup NU author(s): Dr Jill Hunter, Dr Nicola Hannaway, Scott Kerridge, Dr Saimir Luli, 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.

Publication metadata

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


DOI: 10.1042/BCJ20220102

PubMed id: 36240066


Altmetrics provided by Altmetric


Funder referenceFunder name
11022Bloodwise (Formerly Leukaemia and Lymphoma Research)
C1443/A12750Cancer Research UK CRUK (open competition)
C1443/A22095Cancer Research UK CRUK (open competition)
Wellcome Trust