Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

Cho, M.-G.; Kumar, R. J.; Lin, C.-C.; Boyer, J. A.; Shahir, J. A.; Fagan-Solis, K.; Simpson, D. A.; Fan, C.; Foster, C. E.; Goddard, A. M.; Wang, Q.; Wang, Y.; Ho, A. Y.; Liu, P.; perou, c. J.; Zhang, Q.; McGinty, R. K.; Purvis, J. E.; Gupta, G. P.

doi:10.1101/2022.12.09.519750

bioRxiv · 10.1101/2022.12.09.519750

Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

Cho, M.-G.·Kumar, R. J.·Lin, C.-C.·Boyer, J. A.·Shahir, J. A.·Fagan-Solis, K.·Simpson, D. A.·Fan, C.·Foster, C. E.·Goddard, A. M.·Wang, Q.·Wang, Y.·Ho, A. Y.·Liu, P.·perou, c. J.·Zhang, Q.·McGinty, R. K.·Purvis, J. E.·Gupta, G. P.

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Abstract

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS/STING-mediated innate immune signaling and tumor suppression1-3. However, the mechanism for cGAS activation by endogenous DNA damage remains enigmatic, particularly given the constitutive inhibition of cGAS by high-affinity histone acidic patch (AP) binding4-10. Here we report an in vivo CRISPR screen that identified the DNA double strand break sensor Mre11 as a suppressor of mammary tumorigenesis induced by Myc overexpression and p53 deficiency. Mre11 antagonizes Myc-induced proliferation through cGAS/STING activation. Direct binding of the Mre11-Rad50-Nbn (MRN) complex to nucleosomes displaces cGAS from AP sequestration, which is required for DNA damage-induced cGAS mobilization and activation by cytosolic DNA. Mre11 is thereby essential for cGAS activation in response to oncogenic stress, cytosolic DNA transfection, and ionizing radiation. Furthermore, we show Mre11-dependent cGAS activation suppresses Myc-induced proliferation through ZBP1/RIPK3/MLKL-mediated necroptosis. In human triple-negative breast cancer, ZBP1 downregulation correlates with increased genome instability, decreased immune infiltration, and poor patient prognosis. These findings establish Mre11 as a critical link between DNA damage and cGAS activation that regulates tumorigenesis through ZBP1-dependent necroptosis. One-sentence summaryMre11 is required for cGAS activation during oncogenic stress and promotes ZBP1-dependent necroptosis.

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Cho, M.-G., Kumar, R. J., Lin, C.-C., Boyer, J. A., Shahir, J. A., Fagan-Solis, K., Simpson, D. A., Fan, C., Foster, C. E., Goddard, A. M., Wang, Q., Wang, Y., Ho, A. Y., Liu, P., perou, c. J., Zhang, Q., McGinty, R. K., Purvis, J. E., Gupta, G. P.. 2022-12-10. Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis. https://doi.org/10.1101/2022.12.09.519750

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