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Repair of DNA ends with adducts

Award Number: R01GM141631
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: 03/15/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Repair of DNA ends with adducts - Project Summary Environmental pollutants and anti-cancer chemicals induce DNA–protein crosslinks (DPCs, also known as protein adducts) of topoisomerases and other proteins that obstruct almost every chromatin transaction and lead to mutations, genome instability and cell death if not removed quickly. Cells thus possess multiple mechanisms to remove DPCs: homologous recombination, nucleotide excision repair and proteolytic repair that involves proteolysis of bound proteins and nucleolytic cleavage of peptide-DNA bonds. Among these, proteolytic DPC repair is poorly defined and there are many questions about this unique collaboration between protease and nuclease and their substrate recognition. Using genetic and biochemical approaches, we have discovered that Apn2, the evolutionarily conserved back-up AP endonuclease, possesses an enzymatic activity unblocking DNA ends with various 3’ adducts including 2’,3’-cyclic phosphate, monophosphate and tyrosine DNA conjugates. We also found that Apn2 removes DNA-topoisomerase I crosslinks, the flagship DPC at 3' termini. The results might explain several puzzling symptoms in mice deleted for APE2, the metazoan Apn2 homolog, including dys-lymphopoiesis and growth retardation. The results also underscore the importance of 3’ blocked termini processing for genome maintenance and reveal unique challenges in removing these toxic DNA lesions in a tractable model system. Nevertheless, our results also raise a new set of questions about the regulation of Apn2 and APE2 in 3' adduct repair. For instance, we aim to determine how Apn2 recognizes a wide range of 3’ termini with different structural features and how such activities are regulated under unique cellular and functional contexts. We also want to elucidate the biological significance of Apn2 and human APE2-dependent Top1cc repair in cellular physology exposed to chemotherapeutics. Furthermore, we plan to define the roles of Apn2 and its interacting protease(s) in the removal of toxic DNA protein complexes (DPCs) that form via environmental pollutants and chemicals. The current proposal will address these important questions using innovative genetic and biochemical assays and shed light on the fundamental mechanisms of 3’ DNA adduct repair, mutagenesis and maintenance of chromosomal integrity. Emerging evidence suggests that accumulated DPCs cause aging, neurodegeneration and liver cancers. The human homolog of Apn2 is also essential for the viability of BRCA-deficient breast and ovarian cancer cells. The functional conservation in Top1cc and DPC repair between yeast and human further underscores the value of the proposed research in setting the foundation for analyzing the equivalent processes in human. Information gained from our proposed research plan will not only solve one of the fundamental questions in biological processes associated with mutagenesis, DNA repair, and genome maintenance, but will also impinge directly on the management and treatment of patients suffering from several devastating diseases with no clear treatment option.


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 = $310,000 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	4	2/9/2026	NON-COMPETING CONTINUATION	$310,000
														Subtotal = $310,000

Issue Date FY: 2025 ( Subtotal = $310,000 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	001	3	8/6/2025	NON-COMPETING CONTINUATION	$31,000
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	3	2/24/2025	NON-COMPETING CONTINUATION	$279,000
														Subtotal = $310,000

Issue Date FY: 2024 ( Subtotal = $435,695 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	002	2	8/27/2024	SUPPLEMENT FOR EXPANSION	$125,695
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	2	2/13/2024	NON-COMPETING CONTINUATION	$279,000
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	001	2	6/20/2024	NON-COMPETING CONTINUATION	$31,000
														Subtotal = $435,695

Issue Date FY: 2023 ( Subtotal = $310,000 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	1	3/13/2023	NEW	$310,000
														Subtotal = $310,000

Grand Total All Awards = $1,365,695

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Repair of DNA ends with adducts

Award Number: R01GM141631

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: 03/15/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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