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Repair of Environmentally Induced Mitochondrial DNA Damage

Award Number: R01ES030084
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Repair of Environmentally Induced Mitochondrial DNA Damage - Project Summary/ Abstract This proposal connects metabolic dysfunction to the regulation of repair following mitochondrial DNA (mtDNA) damage caused by environmental toxicants. Environmental agents such as ionizing radiation, chemicals found in cigarette smoke, herbicides, and heavy metals as well as normal cellular metabolic processes, generate reactive oxygen species (ROS) in cells. ROS cause damage to cellular DNA, which if not properly repaired, can trigger genome instability and the progression of metabolic diseases including neurodegenerative disorders, aging, and cancer. MtDNA is more susceptible than its nuclear counterpart to oxidative stress. The base excision repair (BER) pathway mends damaged bases in both nuclear and mitochondrial compartments. Specialized enzymes called DNA glycosylases play a critical role in initializing BER by excising damaged bases and mediating other aspects of the repair process via essential protein:protein interactions. We will determine the role and regulation of two DNA glycosylases, NEIL1 and NEIL2, in the repair of mtDNA. We hypothesize that the NEIL enzymes form unique and distinct complexes with mitochondrial proteins that are responsible for mtDNA replication and transcription including mitochondrial single-stranded DNA binding protein (mtSSB), transcription factor A (TFAM), polymerase γ (Polγ), and the twinkle helicase. Our central hypothesis is that complex formation between the NEIL enzymes and mitochondrial proteins drives repair ahead of the replication/ transcription forks and is regulated via (de)acetylation. To address this hypothesis, we will examine the functional interactions between the NEIL enzymes and the named mitochondrial proteins via structure-driven analyses. Experiments using protein painting, small angle-X-ray scattering, and X-ray crystallography will be used to determine the structures of complexes formed between NEIL1, mtSSB, Polγ, and Twinkle as well as between NEIL2, TFAM, and Polγ. Next, we will test the impact of (de)acetylation on NEIL function. High levels of acetyl-coenzyme A in the mitochondrion drives chemical acetylation of proteins and our preliminary data suggests that NEIL2 is modified in this manner. Deacetylation of the NEIL proteins by the NAD+-dependent sirtuin enzymes regulates protein function and will be explored here. Cellular metabolism, mitochondrial dysfunction, and environmental toxicants that cause an increase in ROS levels adversely impact the bioavailability of key metabolites (NAD+) required for deacetylation; a pivotal aspect of our research. Lastly, we will study the localization of the NEIL enzymes under conditions of environmentally induced oxidative stress and their impact on mitochondrial respiration, membrane potential, and morphology. This will shed light on essential nuclear-mitochondrial crosstalk that results from oxidative stress. MtDNA repair is a budding field, with the NEIL enzymes placed at the forefront of the repair process by our recent discoveries. By addressing critical questions of NEIL complex formation, regulation of activity, and localization, the proposed studies will provide the molecular insight necessary for understanding how the repair of mtDNA damage caused by environmental toxicants prevents mutagenesis and offers a novel connection between mitochondrial metabolic function and mtDNA 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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Environmental Health	000	5	4/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $423,500 )
2023	2023	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	5	3/6/2023	NON-COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2022 ( Subtotal = $431,200 )
2022	2022	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	4	3/25/2022	NON-COMPETING CONTINUATION	$431,200
														Subtotal = $431,200

Issue Date FY: 2021 ( Subtotal = $462,000 )
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	3	3/12/2021	NON-COMPETING CONTINUATION	$462,000
														Subtotal = $462,000

Issue Date FY: 2020 ( Subtotal = $423,500 )
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	001	2	4/8/2020	NON-COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	2	3/12/2020	NON-COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2019 ( Subtotal = $523,809 )
2019	2019	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	1	1/2/2019	NEW	$523,809
2019	2019	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Environmental Health	001	1	2/1/2019	NEW	$0
														Subtotal = $523,809

Grand Total All Awards = $2,264,009

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Repair of Environmentally Induced Mitochondrial DNA Damage

Award Number: R01ES030084

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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