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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272107 | GEO | 2025/01/19

REPOSITORIES: GEO

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Gene expression of colorectal cancer cells treated with Celastrol or compound 19-048

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2022-12-31 | GSE198630 | GEO

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2011-01-05 | E-GEOD-25848 | biostudies-arrayexpress

Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation

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Project description:Peroxiredoxin 1 (PRDX1), traditionally known as an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (SAA3) and aconitate decarboxylase 1 (ACOD1), known inhibitors of osteoclast differentiation. Mechanistically, PRDX1-TLR4 signaling activates p65, promoting SAA3 and ACOD1 expression while inhibiting NFATc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from NFATc1 to SAA3/ACOD1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that monomeric variants of PRDX1 with enhanced TLR4 binding exhibit potent inhibition of osteoclast differentiation. Our findings elucidate the inhibitory role of PRDX1-TLR4 axis in osteoclastogenesis, providing insights into therapeutic strategies for bone-related disorders.

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ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

2011-01-05 | GSE25848 | GEO

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

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

| PRJNA1135133 | ENA

Non redundant functions of ATM and DNAPKcs in response to clean DNA Double Strand Breaks.

Project description:DNA Double Strand Breaks (DSBs) are harmful lesions that require rapid detection and repair in order to avoid toxic genomic rearrangements. DSBs elicit the so called DNA Damage Response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA Protein Kinase (DNAPK), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA cell line, expressing the AsiSI restriction enzyme, we have investigated the role of ATM and DNAPK in several aspects of the DDR upon induction of multiple clean DSBs throughout the human genome. High resolution mapping revealed that they are activated and spread in cis on a confined region surrounding all DSBs, independently of the pathway used for repair. However, a thorough analysis of repair kinetics, H2AX domain establishment and H2AX foci structure and dynamics revealed non overlapping functions for the two kinases once recruited at DSBs. Our results suggest that ATM is not solely acting on chromatin marks but also on chromatin organisation in order to ensure repair accuracy and survival.

2015-09-30 | E-MTAB-2992 | biostudies-arrayexpress

ATM-knockout on total and phosphorylation proteomes of cortical brain organoids

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2024-07-25 | PXD041699 | Pride

Influence of ATM-mediated DNA damage response on genomic variation in human induced pluripotent stem cells (Affymetrix expression)

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2016-03-29 | E-GEOD-78716 | biostudies-arrayexpress

DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition

Project description:Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors have not been fully elucidated. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing novel molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.

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