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Mechanisms of AP-Site Identification and Processing at Replication Forks by APE1

Award Number: F31ES038004
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/14/2026
PERIOD OF PERFORMANCE END DATE: 11/13/2027

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Mechanisms of AP-Site Identification and Processing at Replication Forks by APE1 - Project Summary/Abstract Oxidative stress is caused by a variety of environmental toxins in the air, food, and water sources that humans consume on a daily basis. This environmentally induced oxidative stress generates reactive oxygen species that react with DNA to generate oxidative DNA damage. If left unrepaired, oxidative DNA damage can become mutagenic and promote genomic instability, leading to multiple human diseases. The primary defense against oxidative DNA damage is the Base Excision Repair (BER) pathway. During BER, a DNA glycosylase removes the damaged base and leaves behind an apurinic/apyrimidinic site (AP-site), one of the most prevalent forms of oxidative DNA damage. A key multifunctional enzyme of the BER pathway, apurinic/apyrimidinic endonuclease 1 (APE1), is responsible for enzymatically processing AP-sites through nucleolytic cleavage. Interestingly, APE1 has been shown to cleave AP-sites within both the double-stranded and single-stranded DNA regions of replication forks. Importantly, the single-stranded DNA region is highly susceptible to spontaneous DNA damage. However, it remains unclear how APE1 identifies and processes AP-sites at the replication fork. Understanding how APE1 processes AP-sites at replication forks and how replication associated factors, such as replication protein A (RPA), influence APE1 mechanisms will deepen our understanding of how replication-coupled DNA repair maintains genome stability. The goal of this proposal is to determine how APE1 searches for and recognizes AP-sites at replication forks, and understand how replication associated factors impact these mechanisms. To address this, I propose the following aims: (1) determine the APE1 mechanisms for AP-site identification and processing at replication forks, and 2) determine how AP-site processing by APE1 alters replication fork progression and the impact of RPA. To accomplish these aims, I will comprehensively study the mechanisms of APE1 search and recognition, as well as the mechanistic impacts of RPA on these APE1 activities. Specifically, correlative-optical tweezers and fluorescence microscopy (CTFM) will determine the mechanisms APE1 uses to search for and recognize AP-sites at replication forks (Aim 1A) and how RPA impacts these mechanisms (Aim 2B). X-ray crystallography will be used to gain structural insight on AP-site recognition by APE1 on replication fork-like substrates with damage (Aim 1B). Finally, cell-based assays will be used to understand the impact of AP-site processing by APE1 during DNA replication (Aim 2A). These complementary advanced techniques will provide me with outstanding scientific training under the supervision of an expert sponsorship team. In addition to the technical skills, the training plan also prioritizes training in scientific communication, writing, and mentorship. The proposed experiments will provide me with the foundation for a successful research career.


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 = $42,599 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Environmental Health	000	1	5/18/2026	NEW	$42,599
														Subtotal = $42,599

Grand Total All Awards = $42,599

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Mechanisms of AP-Site Identification and Processing at Replication Forks by APE1

Award Number: F31ES038004

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/14/2026

PERIOD OF PERFORMANCE END DATE: 11/13/2027

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