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Defining the mechanistic basis of ATM’s impact on VDJ recombination

Award Number: R01AI147634
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/20/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Defining the mechanistic basis of ATM’s impact on VDJ recombination - Project Summary The ATM kinase is central to the DNA damage response; it follows that this large kinase is central to regulating how developing lymphocytes respond to their self-imposed DNA damage during VDJ recombination. Although the evidence is overwhelming and unequivocal that ATM contributes to accurate non-homologous end joining of VDJ coding segments, and restrains their participation in genomic translocations, a clear mechanistic understanding of how ATM actually does this job is lacking. Recently, we found that ATM ablation in many cultured cell strains results in increased VDJ joining in episomal assays, a completely counter-intuitive result if ATM were to have a direct functional role in end joining. We considered that if ATM's role was instead, to regulate the RAG post cleavage complex(s), loss of ATM might result in increased release of VDJ recombination intermediates and more rapid joining, explaining the increased recombination observed. We fine-tuned the assay so that a structure/function, reductionist approach could be employed to delineate if and how ATM directly affects the RAG complex. We find that ATM inhibition of signal joining requires the non-core C-termini of both RAG1 and RAG2. This prompted an examination of these regions for potential ATM/DNA-PK target sites. Blocking these sites not only blocks ATM's effect on signal joining in cellular assays, it also ablates robust phosphorylation of RAG1/RAG2 on highly purified and fully functional RAG complexes by ATM and DNA-PK in vitro. These data support our model that ATM directly regulates VDJ recombination by phosphorylation of the RAG complex. The experiments proposed in this application will use biochemical approaches to define how ATM affects cleavage and signal end release, and will use a cellular model of chromosomal VDJ recombination to further define how ATM regulates VDJ recombination.


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: 2025 ( Subtotal = $0 )
2025	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	5	3/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $387,500 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	5	4/5/2024	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2023 ( Subtotal = $387,500 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	4	4/11/2023	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	3	5/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $387,500 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	3	4/14/2021	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	2	4/9/2020	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2019 ( Subtotal = $387,500 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	1	5/20/2019	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,937,500

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Defining the mechanistic basis of ATM’s impact on VDJ recombination

Award Number: R01AI147634

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/20/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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