Dataset Information

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

ABSTRACT: Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression^1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)^4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

SUBMITTER: Cho MG

PROVIDER: S-EPMC10794148 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Cho Min-Guk MG Kumar Rashmi J RJ Lin Chien-Chu CC Boyer Joshua A JA Shahir Jamshaid A JA Fagan-Solis Katerina K Simpson Dennis A DA Fan Cheng C Foster Christine E CE Goddard Anna M AM Lerner Lynn M LM Ellington Simon W SW Wang Qinhong Q Wang Ying Y Ho Alice Y AY Liu Pengda P Perou Charles M CM Zhang Qi Q McGinty Robert K RK Purvis Jeremy E JE Gupta Gaorav P GP

Nature 20240110 7995

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression<sup>1-3</sup>. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)<sup>4-10</sup>. Here we report that the DNA double-strand break sensor MRE11 suppre ...[more]

PMID: 38200309

Similar Datasets

Project description:Background & aimsOxidative stress-mediated ferroptosis and macrophage-related inflammation play an important role in various liver diseases. Here, we explored if and how hepatocyte ferroptosis regulates macrophage stimulator of interferon genes (STING) activation in the development of spontaneous liver damage, fibrosis, and tumorigenesis.MethodsWe used a transforming growth factor-beta-activated kinase 1 (TAK1) deficiency-induced model of spontaneous liver damage, fibrosis, and tumorigenesis to investigate hepatocyte ferroptosis and its impact on macrophage STING signalling. Primary hepatocytes and macrophages were used for in vitro experiments.ResultsSignificant liver injury and increased numbers of intrahepatic M1 macrophages were found in hepatocyte-specific TAK1-deficient (TAK1ΔHEP) mice, peaking at 4 weeks and gradually decreasing at 8 and 12 weeks. Meanwhile, activation of STING signalling was observed in livers from TAK1ΔHEP mice at 4 weeks and had decreased at 8 and 12 weeks. Treatment with a STING inhibitor promoted macrophage M2 polarisation and alleviated liver injury, fibrosis, and tumour burden. TAK1 deficiency exacerbated liver iron metabolism in mice with a high-iron diet. Moreover, consistent with the results from single-cell RNA-Seq dataset, TAK1ΔHEP mice demonstrated an increased oxidative response and hepatocellular ferroptosis, which could be inhibited by reactive oxygen species scavenging. Suppression of ferroptosis by ferrostatin-1 inhibited the activation of macrophage STING signalling, leading to attenuated liver injury and fibrosis and a reduced tumour burden. Mechanistically, increased intrahepatic and serum levels of 8-hydroxydeoxyguanosine were detected in TAK1ΔHEP mice, which was suppressed by ferroptosis inhibition. Treatment with 8-hydroxydeoxyguanosine antibody inhibited macrophage STING activation in TAK1ΔHEP mice.ConclusionsHepatocellular ferroptosis-derived oxidative DNA damage promotes macrophage STING activation to facilitate the development of liver injury, fibrosis, and tumorigenesis. Inhibition of macrophage STING may represent a novel therapeutic approach for the prevention of chronic liver disease.Impact and implicationsThe precise mechanism by which hepatocyte ferroptosis regulates macrophage STING activation in the progression of liver damage, fibrosis, and tumorigenesis remains unclear. Herein, we show that deletion of TAK1 in hepatocytes caused oxidative stress-mediated ferroptosis and macrophage-related inflammation in the development of spontaneous liver injury, fibrosis, and hepatocellular carcinoma.

Dataset Information

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Publications

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets