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조민국Min-Guk Cho (Minguk Jo)

University of North Carolina at Chapel Hill

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Nature, Jan 10 2024, | https://doi.org/10.1038/s41586-023-06889-6 MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

Min-Guk Cho^1,11, Rashmi J. Kumar^1,2,11, Chien-Chu Lin³, Joshua A. Boyer⁴, Jamshaid A. Shahir⁵, Katerina Fagan-Solis¹, Dennis A. Simpson¹, Cheng Fan¹, Christine E. Foster¹, Anna M. Goddard^1,6, Lynn M. Lerner^1,7, Simon W. Ellington¹, Qinhong Wang¹, Ying Wang^1,7, Alice Y. Ho⁸, Pengda Liu^1,4, Charles M. Perou^1,7,9, Qi Zhang^1,4, Robert K. McGinty^1,3,4, Jeremy E. Purvis^1,7,9 & Gaorav P. Gupta^1,2,4,7,10

¹Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

²UNC MD–PhD Program, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

³Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁴Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁵Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁶Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁷Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁸Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.

⁹Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

¹⁰Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

¹¹These authors contributed equally: Min-Guk Cho, Rashmi J. Kumar.

Corresponding author : Correspondence to Gaorav P. Gupta.

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-15)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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