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Innovative Nanobody Tools for NEIL1 and NEIL2: Overcoming Barriers in DNA Repair Research

Award Number: R03ES038960
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: 08/05/2026
PERIOD OF PERFORMANCE END DATE: 08/04/2028

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Innovative Nanobody Tools for NEIL1 and NEIL2: Overcoming Barriers in DNA Repair Research - ABSTRACT Oxidative DNA damage caused by environmental exposures and endogenous reactive oxygen species is a major threat to genome integrity and is strongly linked to cancer, neurodegeneration, and aging. Repair of these lesions is initiated by the base excision repair (BER) pathway, where the NEIL1 and NEIL2 DNA glycosylases excise oxidized bases from diverse DNA structures in both the nucleus and mitochondria. Despite their central roles in preserving genome stability, NEIL1 and NEIL2 remain poorly understood because they are expressed at low cellular levels, contain extensive disordered regions, and lack reliable commercial antibody reagents; barriers that have prevented structural and mechanistic studies. This R03 proposal overcomes these limitations by developing and characterizing novel single-domain antibodies (nanobodies) tailored to NEIL1 and NEIL2. Nanobodies provide clear advantages over conventional antibodies: they are small, highly specific, exceptionally stable, and uniquely capable of stabilizing flexible protein regions, enabling both structural studies and live-cell enzyme tracking upon induced DNA damage. We have already generated a panel of NEIL1 nanobodies, one of which stabilizes NEIL1 and permits real-time imaging of its recruitment to laser-induced oxidative DNA damage. Complementing this, an institutional seed grant has enabled initiation of NEIL2 nanobody development, establishing feasibility and strong local commitment. Aim 1 will rigorously benchmark the NEIL1 nanobody panel, quantifying binding affinity and kinetics with biophysical assays and testing effects on glycosylase activity and recruitment upon induced DNA damage. Aim 2 will generate and validate the first NEIL2-specific nanobodies using the same pipeline, creating matched tools for both enzymes. The expected outcome is a set of high-affinity, epitope-defined nanobodies that (i) overcome long-standing experimental barriers, (ii) enable structural and mechanistic dissection of NEIL1/2 in vitro, and (iii) unlock future studies of DNA repair dynamics in living cells upon environmentally-induced DNA damage. All sequences, plasmids, and protocols will be broadly shared. By delivering these enabling reagents, this project will resolve persistent technical barriers, establish the first nanobody toolkit for NEIL glycosylases, and empower the DNA repair community to probe fundamental mechanisms of genome stability.


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 = $156,000 )
2026	2026	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BLVD	MOBILE	AL	36688	MOBILE	USA	Environmental Health	000	1	8/4/2026	NEW	$156,000
														Subtotal = $156,000

Grand Total All Awards = $156,000

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Innovative Nanobody Tools for NEIL1 and NEIL2: Overcoming Barriers in DNA Repair Research

Award Number: R03ES038960

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: 08/05/2026

PERIOD OF PERFORMANCE END DATE: 08/04/2028

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