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Mechanism of APE2 in genome integrity

Award Number: R03CA270663
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mechanism of APE2 in genome integrity - Project Summary/Abstract Environmental toxins or endogenous insults such as reactive oxygen species (ROS) result in oxidative stress within cells, leading to different types of damage in DNA or RNA, including Apurinic/apyrimidinic (AP) sites and single-strand breaks (SSBs). As the most common type of DNA damage, SSBs have been implicated in association with tumorigenesis, aging, and neurodegenerative disorders. Molecular understanding of SSB repair pathway remains unclear, largely due to the lack of tractable experimental systems. We and others have demonstrated recently that APE2 resolves SSB damage in Xenopus and budding yeast. Although APE1 has been found critical for including DNA repair, redox regulation of transcription, and RNA processing, it remains unclear how APE2 plays important roles in DNA and RNA metabolism. It is significant to determine how APE2 plays an essential role in SSB repair, and how exactly APE2 maintains genome stability. Our substantial preliminary data suggest that APE2’s 3'-5' exonuclease activity is regulated via its dynamic interactions with single-strand DNA (ssDNA) and its interacting proteins, and that APE2 associates with RNA and RNA-containing structures such as R-loop. We will dissect the molecular mechanism of APE2 in metabolism in nucleic acids via two Specific Aims: (1) determine the mechanism of how APE2 interacts with and processes AP sites and SSBs in DNA structures in reconstitution system with purified proteins and in Xenopus egg extracts, and (2) determine how APE2 recognizes and repairs AP site and SSBs in RNA or RNA-containing structures. Biochemical, cell biology, and molecular biology approaches will be utilized to conduct this hypothesis-driven structure-function analysis of APE2-mediated metabolism of nucleic acids in Xenopus egg extracts and reconstitution systems with purified proteins. Anticipated results from this project will make a paradigm shift on APE2- mediated SSB repair in DNA/RNA metabolism to maintain genome stability. Notably, our findings will provide novel insights into new strategies for cancer chemotherapies such as modulating the distinct regulatory mechanisms of APE2 for SSB repair in genome integrity.


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 NORTH CAROLINA AT CHARLOTTE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	2	10/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $74,321 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	2	11/20/2023	NON-COMPETING CONTINUATION	$74,321
														Subtotal = $74,321

Issue Date FY: 2023 ( Subtotal = $74,333 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Cause and Prevention Research	000	1	12/15/2022	NEW	$74,333
														Subtotal = $74,333

Grand Total All Awards = $148,654

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Mechanism of APE2 in genome integrity

Award Number: R03CA270663

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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