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Effect of CRISPRi-based depletion of IREB2, MRGBP, and PAX7 on gene expression in A549 dCas9-KRAB cells

ABSTRACT: The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Through orthogonal CRISPRi screens with diverse DDR inhibitors (DDRi) we find a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Loss of IREB2 is believed to reduce free iron levels in cells by repressing translation of the transferrin receptor, and therefore iron uptake, and by promoting ferritin translation to increase iron storage capacity. As PAX7 and MRGBP are both associated with gene expression, we performed bulk RNA-seq in A549 dCas9-KRAB cells expressing sgRNAs targeting IREB2, PAX7, and MRGBP. Strikingly, in all three instances, IREB2 was one of the most downregulated genes. In addition, knockdown of PAX7 led to downregulation of MRGBP and knockdown of MRGBP to downregulation of PAX7. Together, these data indicate that PAX7 and MRGBP cooperate to regulate expression of IREB2 and demonstrate the MRGBP-PAX7-IREB2 as a driver of resistance to DDRi through convergence on IREB2 expression and thus the control of cellular iron levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320129 | GEO | 2026/08/24

REPOSITORIES: GEO

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A chemical-genetic interaction map of the DNA damage response

Project description:The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Here we present data from 32 genome-scale loss-of-function CRISPRi chemical-genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK, and WEE1), as both single agents and in combination with PARP inhibitors. These experiments identify >1000 genes whose perturbation modifies the DDR and provides a rich resource to the DDR community. In addition, this compendium of functional genomics data reveals key principles governing the DDR and highlights a strong chemical-genetic interaction between loss of activity of the peroxiredoxin PRDX1 and all tested DDR inhibitors through a mechanism involving iron availability mediated by an MRGBP-PAX7-IREB2 axis. Our data position PRDX1 as a key suppressor of DNA damage accumulation and potential druggable target in combination with DDR inhibitors.

2026-08-24 | GSE320153 | GEO

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