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Defining the impact of MRE11 and Artemis pathogenic variants on DNA repair, lymphocyte development, and disease-associated phenotypes

Award Number: F31HL182031
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/23/2026
PERIOD OF PERFORMANCE END DATE: 12/22/2027

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Defining the impact of MRE11 and Artemis pathogenic variants on DNA repair, lymphocyte development, and disease-associated phenotypes - PROJECT SUMMARY/ABSTRACT The efficient and accurate repair of DNA double strand breaks (DSBs) is crucial for maintaining genome stability. Defects in repair of these highly detrimental lesions can lead to accumulation of aberrant chromosomal events and/or unrepaired breaks that can have catastrophic consequences for cells and cause human disease. While much has been learned about the three major DNA DSB repair pathways, many questions remain regarding the interplay between proteins that act in multiple pathways and how specific defects in repair processes result in distinct disease outcomes. Without this knowledge, there remains an incomplete understanding of how the integrity of the genome is maintained. The goals of this F31 proposal are to define the relationship between two key DNA nucleases, Artemis and MRE11, in their basic functions and in human disease. Artemis has primary functions in non-homologous end joining (NHEJ), whereas MRE11 has functions in all major DNA DSB pathways, including NHEJ. Partial loss of function mutations in Artemis and MRE11 cause human syndromes that are inherited in a recessive Mendelian fashion. These syndromes can have variable degrees of cancer predisposition, developmental delay, cognitive impairment, and immunodeficiency. Both Artemis and MRE11 possess intrinsic exo- and endonucleolytic activities that process DNA ends at DNA DSBs. In vitro studies with purified proteins have demonstrated overlapping activites, yet studies of patients and animal models with mutations in one or the other gene suggest distinct functions in vivo. We have developed novel mouse models harboring mutations in Artemis or Mre11 that recapitulate human patient phenotypes. The Aims of the proposed studies are to determine the impact of Artemis and Mre11 hypomorphs alone and in combination on repair of DNA ends generated during the lymphocyte specific DNA rearrangement, V(D)J recombination, and via other mechanisms, including ionizing radiation and induced site-specific breaks outside of the V(D)J loci. The research will take advantage of a combination of mouse genetics, molecular and cellular assays, and bioinformatic analyses to characterize normal and aberrant DNA rearrangements, DNA end processing, lymphocyte development, cell cycle checkpoint activation and potentially tumorigenesis. The findings of this research will provide novel insights into the molecular underpinnings of disease caused by Artemis and MRE11 hypomorphic alleles as well as reveal functional interactions between these nucleases during DSB repair.


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 = $44,661 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	6/30/2026	NEW	$44,661
														Subtotal = $44,661

Grand Total All Awards = $44,661

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Defining the impact of MRE11 and Artemis pathogenic variants on DNA repair, lymphocyte development, and disease-associated phenotypes

Award Number: F31HL182031

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/23/2026

PERIOD OF PERFORMANCE END DATE: 12/22/2027

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