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Structural and Mechanistic Insights into AAV Rep Mediated Site-Specific Integration and Packaging

Award Number: R01GM124204
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: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Structural and Mechanistic Insights into AAV Rep Mediated Site-Specific Integration and Packaging - PROJECT SUMMARY Adeno-Associated Virus (AAV) has evolved the property to integrate into its host genome exploiting a unique mechanism shared by organisms in all domains of life to process single stranded DNA during DNA replication, bacterial conjugation and special cases of transposition. The large AAV Rep proteins Rep68/Rep78 are the key players that carry out this process using two multifunctional domains that include an origin binding domain (OBD) that binds DNA specifically and belongs to the family of HUH endonucleases; and a SF3 helicase domain. Integration is contingent on the binding of Rep68/Rep78 to the integration site AAVS1, promote its melting and perform a strand-specific transesterification reaction in the single-stranded region that has been extruded during the melting step. Little is known about the molecular details of this process and our long-term goal is to determine the molecular mechanism of site-specific integration mediated by AAV Rep proteins. In this proposal we will focus on uncovering the mechanisms of Rep mediated DNA melting, nicking and packaging using a combination of structural biology methods that include X-ray crystallography, and single- particle reconstruction Cryo-EM coupled to biochemical, biophysical and in vivo assays.


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 = $293,423 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	8	11/21/2024	NON-COMPETING CONTINUATION	$293,423
														Subtotal = $293,423

Issue Date FY: 2024 ( Subtotal = $326,025 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	7	10/30/2023	NON-COMPETING CONTINUATION	$293,423
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	7	6/17/2024	NON-COMPETING CONTINUATION	$32,602
														Subtotal = $326,025

Issue Date FY: 2023 ( Subtotal = $341,854 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	6	11/3/2022	NON-COMPETING CONTINUATION	$307,668
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	6	2/16/2023	NON-COMPETING CONTINUATION	$34,186
2023	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	5	11/2/2022	COMPETING CONTINUATION	$0
														Subtotal = $341,854

Issue Date FY: 2022 ( Subtotal = $436,340 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	5	12/15/2021	COMPETING CONTINUATION	$343,889
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	5	3/6/2022	COMPETING CONTINUATION	$0
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	003	5	8/11/2022	SUPPLEMENT FOR EXPANSION	$92,451
2022	2020	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	4	3/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $436,340

Issue Date FY: 2020 ( Subtotal = $298,625 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	4	7/29/2020	NON-COMPETING CONTINUATION	$298,625
														Subtotal = $298,625

Issue Date FY: 2019 ( Subtotal = $385,645 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	3	7/30/2019	NON-COMPETING CONTINUATION	$298,801
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	3	8/6/2019	SUPPLEMENT FOR EXPANSION	$86,844
														Subtotal = $385,645

Issue Date FY: 2018 ( Subtotal = $298,547 )
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	2	7/17/2018	NON-COMPETING CONTINUATION	$298,547
														Subtotal = $298,547

Issue Date FY: 2017 ( Subtotal = $293,060 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	1	9/19/2017	NEW	$293,060
														Subtotal = $293,060

Grand Total All Awards = $2,673,519

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Structural and Mechanistic Insights into AAV Rep Mediated Site-Specific Integration and Packaging

Award Number: R01GM124204

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: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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