Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

Haojian Li; Takashi Furusawa; Renzo Cavero; Yunjie Xiao; Raj Chari; Xiaolin Wu; David Sun; Oliver Hartmann; Anjali Dhall; Ronald Holewinski; Thorkell Andresson; Baktiar Karim; Marina Villamor-Payà; Devorah Gallardo; Chi Ping Day; Lipika R. Pal; Nishanth Ulhas Nair; Eytan Ruppin; Mirit I. Aladjem; Yves Pommier; Markus E. Diefenbacher; Jung Mi Lim; Rodney L. Levine; Travis H. Stracker; Urbain Weyemi

doi:10.1016/j.redox.2025.103503

Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

Haojian Li, Takashi Furusawa, Renzo Cavero, Yunjie Xiao, Raj Chari, Xiaolin Wu, David Sun, Oliver Hartmann, Anjali Dhall, Ronald Holewinski, Thorkell Andresson, Baktiar Karim, Marina Villamor-Payà, Devorah Gallardo, Chi Ping Day, Lipika R. Pal, Nishanth Ulhas Nair, Eytan Ruppin, Mirit I. Aladjem, Yves PommierMarkus E. Diefenbacher, Jung Mi Lim, Rodney L. Levine, Travis H. Stracker, Urbain Weyemi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.

Original language	English
Article number	103503
Journal	Redox Biology
Volume	80
DOIs	https://doi.org/10.1016/j.redox.2025.103503
State	Published - Mar 2025
Externally published	Yes

Funding

Funders	Funder number
U.S. Government
NIH Library Editing Service
National Cancer Institute
U.S. Department of Health and Human Services
National Institutes of Health	75N91019D00024
DKH	DIP DI 931/18, 70112013

Keywords

ATM kinase
Disulfide stress
Peroxiredoxin 1
RPL32 redox modification
p53 activation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.redox.2025.103503

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Li, H., Furusawa, T., Cavero, R., Xiao, Y., Chari, R., Wu, X., Sun, D., Hartmann, O., Dhall, A., Holewinski, R., Andresson, T., Karim, B., Villamor-Payà, M., Gallardo, D., Day, C. P., Pal, L. R., Nair, N. U., Ruppin, E., Aladjem, M. I., ... Weyemi, U. (2025). Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition. Redox Biology, 80, Article 103503. https://doi.org/10.1016/j.redox.2025.103503

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title = "Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition",

abstract = "Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.",

keywords = "ATM kinase, Disulfide stress, Peroxiredoxin 1, RPL32 redox modification, p53 activation",

author = "Haojian Li and Takashi Furusawa and Renzo Cavero and Yunjie Xiao and Raj Chari and Xiaolin Wu and David Sun and Oliver Hartmann and Anjali Dhall and Ronald Holewinski and Thorkell Andresson and Baktiar Karim and Marina Villamor-Pay{\`a} and Devorah Gallardo and Day, {Chi Ping} and Pal, {Lipika R.} and Nair, {Nishanth Ulhas} and Eytan Ruppin and Aladjem, {Mirit I.} and Yves Pommier and Diefenbacher, {Markus E.} and Lim, {Jung Mi} and Levine, {Rodney L.} and Stracker, {Travis H.} and Urbain Weyemi",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = mar,

doi = "10.1016/j.redox.2025.103503",

language = "אנגלית",

volume = "80",

journal = "Redox Biology",

issn = "2213-2317",

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Li, H, Furusawa, T, Cavero, R, Xiao, Y, Chari, R, Wu, X, Sun, D, Hartmann, O, Dhall, A, Holewinski, R, Andresson, T, Karim, B, Villamor-Payà, M, Gallardo, D, Day, CP, Pal, LR, Nair, NU, Ruppin, E, Aladjem, MI, Pommier, Y, Diefenbacher, ME, Lim, JM, Levine, RL, Stracker, TH & Weyemi, U 2025, 'Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition', Redox Biology, vol. 80, 103503. https://doi.org/10.1016/j.redox.2025.103503

TY - JOUR

T1 - Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

AU - Li, Haojian

AU - Furusawa, Takashi

AU - Cavero, Renzo

AU - Xiao, Yunjie

AU - Chari, Raj

AU - Wu, Xiaolin

AU - Sun, David

AU - Hartmann, Oliver

AU - Dhall, Anjali

AU - Holewinski, Ronald

AU - Andresson, Thorkell

AU - Karim, Baktiar

AU - Villamor-Payà, Marina

AU - Gallardo, Devorah

AU - Day, Chi Ping

AU - Pal, Lipika R.

AU - Nair, Nishanth Ulhas

AU - Ruppin, Eytan

AU - Aladjem, Mirit I.

AU - Pommier, Yves

AU - Diefenbacher, Markus E.

AU - Lim, Jung Mi

AU - Levine, Rodney L.

AU - Stracker, Travis H.

AU - Weyemi, Urbain

PY - 2025/3

Y1 - 2025/3

N2 - Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.

AB - Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.

KW - ATM kinase

KW - Disulfide stress

KW - Peroxiredoxin 1

KW - RPL32 redox modification

KW - p53 activation

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U2 - 10.1016/j.redox.2025.103503

DO - 10.1016/j.redox.2025.103503

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 39854937

AN - SCOPUS:85215539089

SN - 2213-2317

VL - 80

JO - Redox Biology

JF - Redox Biology

M1 - 103503

ER -

Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

Abstract

Funding

Keywords

UN SDGs

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