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Elucidating the Mechanisms of MRE11-Mediated cGAS Activation in DNA Sensing: Mechanisms of cGAS Activation

Award Number: K22CA303691
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Elucidating the Mechanisms of MRE11-Mediated cGAS Activation in DNA Sensing: Mechanisms of cGAS Activation - PROJECT SUMMARY/ABSTRACT The cGAS-STING pathway plays a crucial role in initiating the innate immune response by recognizing cytosolic double-stranded DNA (dsDNA) resulting from oncogene-induced DNA damage, leading to the elimination of damaged or cancerous cells. MRE11, a DNA repair protein, facilitates the release of cGAS from chromatin, enabling it to detect cytosolic dsDNA or micronuclear (MN) DNA and activate the STING pathway. However, the mechanisms by which MRE11 mediates cGAS release and how cGAS recognizes and responds to dsDNA and MN remain unclear. Recent studies suggest that nuclear envelope rupture alone is insufficient for cGAS recruitment to MN, and histone modifications such as H3K79me2 play a crucial role in cGAS activation within MN. The goal of this study is to determine how cGAS is released and activated by MRE11 and to identify other interacting proteins that clarify the mechanisms of MRE11-mediated cGAS activation. Aim 1 focuses on how specific histone modifications, such as H3K79me2 and H3K27ac, influence cGAS release from chromatin through interactions with MRE11, facilitating its relocation to cytosolic dsDNA and MN. We will utilize histone methylation inhibitors, siRNA, and CRISPR/Cas9-based gene knockdown or chromatin immunoprecipitation (ChIP) assays to investigate this, alongside in vitro experiments with modified nucleosomes to assess the binding affinity between MRE11 and cGAS. Aim 2 investigates whether additional regulatory steps are required for full cGAS activation, building on previous data that suggest cytoplasmic translocation and dsDNA sensing alone are insufficient. We will use R255A mutants and cGAS variants with nuclear localization signals (NLS) or nuclear export signals (NES) to explore mechanisms required for STING pathway activation. Aim 3 involves creating stable cell lines expressing BioID2-tagged cGAS and MRE11 to map their interaction networks and identify proteins involved in cGAS-MRE11 interactions through proteomics. Identified proteins will be assessed for their roles in modulating cGAS activation and downstream signaling, revealing potential therapeutic targets. This study aims to elucidate the molecular mechanisms of cGAS-STING pathway-mediated tumor suppression, potentially offering new therapeutic strategies to enhance immune responses in cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $223,938 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Research Manpower	000	1	8/31/2026	NEW	$223,938
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Research Manpower	001	1	9/17/2026	NEW	$0
														Subtotal = $223,938

Grand Total All Awards = $223,938

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Elucidating the Mechanisms of MRE11-Mediated cGAS Activation in DNA Sensing: Mechanisms of cGAS Activation

Award Number: K22CA303691

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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