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Genome-wide CRISPR screening identifies a role for ARRDC3 in TRP53-mediated responses

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posted on 2024-02-21, 03:36 authored by John La-MarcaJohn La-Marca, BJ Aubrey, B Yang, C Chang, Z Wang, Andrew Kueh, Lin Tai, S Wilcox, L Milla, Susanne Heinzel, D Vremec, L Whelan, C König, D Kaloni, AK Voss, A Strasser, Sarah DiepstratenSarah Diepstraten, Marco HeroldMarco Herold, GL Kelly
Whole-genome screens using CRISPR technologies are powerful tools to identify novel tumour suppressors as well as factors that impact responses of malignant cells to anti-cancer agents. Applying this methodology to lymphoma cells, we conducted a genome-wide screen to identify novel inhibitors of tumour expansion that are induced by the tumour suppressor TRP53. We discovered that the absence of Arrestin domain containing 3 (ARRDC3) increases the survival and long-term competitiveness of MYC-driven lymphoma cells when treated with anti-cancer agents that activate TRP53. Deleting Arrdc3 in mice caused perinatal lethality due to various developmental abnormalities, including cardiac defects. Notably, the absence of ARRDC3 markedly accelerated MYC-driven lymphoma development. Thus, ARRDC3 is a new mediator of TRP53-mediated suppression of tumour expansion, and this discovery may open new avenues to harness this process for cancer therapy.

Funding

This work was supported by fellowships and grants from the Australian National Health and Medical Research Council (NHMRC) (Program Grant GNT1113133 to AS, Research Fellowships GNT1156095 to MJH, GNT1116937 to AS, and GNT1081421 to AKV, Project Grants GNT1159658, GNT1186575, and GNT1145728 to MJH, GNT1143105 to MJH and AS, and GNT1127198 to SH (and Phil Hodgkin, WEHI), Ideas Grants GNT2002618 and GNT2001201 to GLK, Synergy Grants GNT2011139 to GLK and GNT2010275 to AS), the Leukemia & Lymphoma Society of America (Specialized Center of Research grant no. 7015-18 to MJH, AS, and GLK), Cancer Council Victoria Venture Grant to MJH and AS, Victorian Cancer Agency (MCRF Fellowship 17028 to GLK and ECRF Fellowship 21006 to STD), CASS Foundation Grants (to STD and JELM), the estate of Anthony (Toni) Redstone OAM (AS and GLK), the Craig Perkins Cancer Research Foundation (GLK), the Dyson Bequest (GLK) and the Harry Secomb Foundation (GLK), a donation from Robert and Janette Boffey (JELM), and operational infrastructure grants through the Victorian State Government Operational Infrastructure Support (OIS) and Australian Government NHMRC Independent Research Institute Infrastructure Support (IRIIS) Schemes. The generation of Arrdc3 knockout mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program

History

Publication Date

2024-02-01

Journal

Cell Death and Differentiation

Volume

31

Issue

2

Pagination

9p. (p. 150-158)

Publisher

Springer Nature

ISSN

1350-9047

Rights Statement

© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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