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Mechanisms of BER in Genomic Integrity and Epigenetic Regulation

Award Number: R35GM136225
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Mechanisms of BER in Genomic Integrity and Epigenetic Regulation - An overarching goal of our research is to understand how the base excision repair (BER) pathway maintains genomic integrity and mediates epigenetic regulation, and how deficiencies in BER impact human health. A major focus is to discover how DNA glycosylases, which initiate BER, find and excise damaged or modified forms of 5-methylcytosine (mC). The most abundant modified DNA base in nature, mC is critical for epigenetic regulation in plants and animals and for restriction modification in archaea and bacteria. However, cytosine methylation also poses a danger because mC deaminates to T, generating G/T mispairs and C to T mutations that threaten genomic and epigenetic integrity and causes human diseases including cancer. Countering this threat are three different types of glycosylases that excise T from G/T mispairs; TDG and MBD4 in mammals and MIG in archaea and bacteria. While most glycosylases excise bases that are foreign to DNA (e.g., uracil) these enzymes face the daunting task of removing thymine bases arising by mC deamination but not those in the vast background of A:T pairs or in polymerase-generated G/T mispairs. Because glycosylase action on undamaged DNA is mutagenic, the specificity of these G/T glycosylases is critical, yet it is poorly defined. The current paradigm holds that specificity involves recognition of the mismatched guanine. We will rigorously test this model and investigate other potential specificity factors, to define the mechanism of G/T glycosylase specificity. Our studies will reveal features of TDG and MBD4 that may account for inefficient repair of mC deamination, a potential cause of point mutations implicated in cancer and genetic disease. BER also functions in epigenetic regulation by serving to “erase” mC through active DNA demethylation. An established pathway in vertebrates involves oxidation of mC by a TET enzyme to give three oxy-mC products (hmC, fC, caC), excision of fC or caC by TDG, and subsequent BER to yield unmodified C. Our studies will address major gaps in the understanding of this essential pathway, by defining how TDG recognizes and removes fC and caC and how it is recruited to sites of DNA demethylation. We are also interested in how post-translational modifications regulate BER, and our current focus is on determining how TDG is regulated by SUMO modification. TDG is sumoylated at a single site, and it has a SUMO-interacting motif (SIM) that binds SUMO domains, including an intramolecular SUMO. While TDG is considered a model for understanding how sumoylation can regulate enzyme activity, many fundamental questions remain. Our studies will reveal how sumoylation alters TDG activity and how the SIM mediates these effects. We will also define mechanisms of SUMO conjugation and deconjugation and learn how the SIM modulates these processes. An in vitro conjugation-deconjugation system will be used to test the paradigm that sumoylation of TDG is required to regulate its product release and ensure faithful completion of TDG-initiated BER. Results of these studies will inform how BER deficiencies impact human health and could suggest new therapeutic approaches for treating diseases including 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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $463,694 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	5	7/17/2024	NON-COMPETING CONTINUATION	$38,050
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	5	6/19/2024	SUPPLEMENT FOR EXPANSION	$83,201
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	4/10/2024	NON-COMPETING CONTINUATION	$342,443
														Subtotal = $463,694

Issue Date FY: 2023 ( Subtotal = $539,242 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	4	7/28/2023	SUPPLEMENT FOR EXPANSION	$113,915
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	4	4/26/2023	SUPPLEMENT FOR EXPANSION	$44,834
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	4/24/2023	NON-COMPETING CONTINUATION	$380,493
														Subtotal = $539,242

Issue Date FY: 2022 ( Subtotal = $455,217 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	003	3	6/23/2022	NON-COMPETING CONTINUATION	$97,828
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	004	3	6/29/2022	NON-COMPETING CONTINUATION	-$59,779
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	3	4/9/2022	SUPPLEMENT FOR EXPANSION	$59,779
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	1/12/2022	SUPPLEMENT FOR EXPANSION	$14,945
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	4/8/2022	NON-COMPETING CONTINUATION	$342,444
														Subtotal = $455,217

Issue Date FY: 2021 ( Subtotal = $517,392 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	2	8/30/2021	SUPPLEMENT FOR EXPANSION	$136,899
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	4/9/2021	NON-COMPETING CONTINUATION	$380,493
														Subtotal = $517,392

Issue Date FY: 2020 ( Subtotal = $380,493 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	3/12/2020	NEW	$380,493
														Subtotal = $380,493

Grand Total All Awards = $2,356,038

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Mechanisms of BER in Genomic Integrity and Epigenetic Regulation

Award Number: R35GM136225

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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