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Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

FromPaperPlayer biorxiv cell biology


Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

FromPaperPlayer biorxiv cell biology

ratings:
Length:
20 minutes
Released:
Dec 10, 2022
Format:
Podcast episode

Description

Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.09.519750v1?rss=1

Authors: 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.

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.

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Podcast created by Paper Player, LLC
Released:
Dec 10, 2022
Format:
Podcast episode

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