NBS1-CtIP-mediated DNA end resection suppresses cGAS binding to micronuclei

Salim Abdisalaam, Shibani Mukherjee, Souparno Bhattacharya, Sharda Kumari, Debapriya Sinha, Janice Ortega Rodriguez, Guo Min Li, Hesham A. Sadek, Sunil Krishnan, Aroumougame Asaithamby

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclic guanosine monophosphate-Adenosine monophosphate synthase (cGAS) is activated in cells with defective DNA damage repair and signaling (DDR) factors, but a direct role for DDR factors in regulating cGAS activation in response to micronuclear DNA is still poorly understood. Here, we provide novel evidence that Nijmegen breakage syndrome 1 (NBS1) protein, a well-studied DNA double-strand break (DSB) sensor-in coordination with Ataxia Telangiectasia Mutated (ATM), a protein kinase, and Carboxy-Terminal binding protein 1 interacting protein (CtIP), a DNA end resection factor-functions as an upstream regulator that prevents cGAS from binding micronuclear DNA. When NBS1 binds to micronuclear DNA via its fork-head-Associated domain, it recruits CtIP and ATM via its N-and C-Terminal domains, respectively. Subsequently, ATM stabilizes NBS1's interaction with micronuclear DNA, and CtIP converts DSB ends into single-strand DNA ends; these two key events prevent cGAS from binding micronuclear DNA. Additionally, by using a cGAS tripartite system, we show that cells lacking NBS1 not only recruit cGAS to a major fraction of micronuclear DNA but also activate cGAS in response to these micronuclear DNA. Collectively, our results underscore how NBS1 and its binding partners prevent cGAS from binding micronuclear DNA, in addition to their classical functions in DDR signaling.

Original languageEnglish (US)
Pages (from-to)2681-2699
Number of pages19
JournalNucleic acids research
Volume50
Issue number5
DOIs
StatePublished - Mar 21 2022

ASJC Scopus subject areas

  • Genetics

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