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Suppression of duplication-mediated genome rearrangements by protein sumoylation

Award Number: R01GM116897
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: 09/30/2015
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Suppression of duplication-mediated genome rearrangements by protein sumoylation - Project summary Genome rearrangements are mutations that cause numerous genetic diseases including cancer, immune deficiencies and developmental disorders. Genome rearrangements are caused by defects in DNA replication and repair pathways, as well as the presence of numerous at-risk sequences in the human genome that are prone to mutations. Protein sumoylation is reversible and involves the opposing actions of two families of enzymes; the E3 ligases that catalyze the attachment of Small Ubiquitin-like MOdifier (SUMO) to substrates, and the SUMO specific proteases that remove them. Our genetic study using Saccharomyces cerevisiae has identified a major role of these enzymes in preventing diverse genome rearrangements, and has further uncovered a new paradigm in which spontaneous DNA breaks occurred during DNA replication caused these genome rearrangements. Additionally, results from our proteomic and biochemical studies have identified the Mini-Chromosome Maintenance (MCM) complex at the DNA replication fork as a major target under the regulation of SUMO. Because inherited mutations of genes in the SUMO pathways cause genome instability syndrome in mammals, understanding the molecular basis by which protein sumoylation regulates DNA replication will impact human health for two major reasons: 1) a comprehensive understanding of the genetic consequences that arise from mutations to the SUMO pathways, with regards to DNA replication, will impact the development of assays for cancer diagnosis. 2) Identifying the molecular mechanism by which SUMO regulates DNA replication will lead to the development of new therapeutic interventions of human disease. Thus, in the proposed studies we will characterize the genetics and biochemistry of the SUMO pathways in the model organism S. cerevisiae. We will pursue the following specific aims: First, we will characterize the function of protein sumoylation during chromosomal DNA replication. Second, we will investigate the role of SUMO and ubiquitin in regulating DNA replication. And finally, we will study how reversible sumoylation of the DNA replisome is regulated. The ultimate goal is to understand how SUMO regulates DNA replication and how cells utilize this pathway to prevent genome rearrangements.


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	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	8/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $336,088 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	3/29/2023	NON-COMPETING CONTINUATION	$324,086
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	5/3/2023	SUPPLEMENT FOR EXPANSION	$12,002
														Subtotal = $336,088

Issue Date FY: 2022 ( Subtotal = $324,086 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	8/1/2022	NON-COMPETING CONTINUATION	$32,411
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	3/16/2022	NON-COMPETING CONTINUATION	$291,675
														Subtotal = $324,086

Issue Date FY: 2021 ( Subtotal = $324,086 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	3/2/2021	NON-COMPETING CONTINUATION	$324,086
2021	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	5/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $324,086

Issue Date FY: 2020 ( Subtotal = $323,831 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	3/23/2020	COMPETING CONTINUATION	$323,831
2020	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	3/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $323,831

Issue Date FY: 2019 ( Subtotal = $6,024 )
2019	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	3/5/2019	NON-COMPETING CONTINUATION	-$306,881
2019	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	003	4	5/13/2019	NON-COMPETING CONTINUATION	-$4,919
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	004	5	5/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$71,556
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	3/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$312,905
2019	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	3	5/13/2019	NON-COMPETING CONTINUATION	-$66,637
														Subtotal = $6,024

Issue Date FY: 2018 ( Subtotal = $311,800 )
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	8/30/2018	NON-COMPETING CONTINUATION	$311,800
														Subtotal = $311,800

Issue Date FY: 2017 ( Subtotal = $311,800 )
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	8/16/2017	NON-COMPETING CONTINUATION	$311,800
														Subtotal = $311,800

Issue Date FY: 2016 ( Subtotal = $372,146 )
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	8/16/2016	SUPPLEMENT FOR EXPANSION	$60,346
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	8/9/2016	NON-COMPETING CONTINUATION	$311,800
														Subtotal = $372,146

Issue Date FY: 2015 ( Subtotal = $311,800 )
2015	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	9/23/2015	NEW	$311,800
														Subtotal = $311,800

Grand Total All Awards = $2,621,661

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Suppression of duplication-mediated genome rearrangements by protein sumoylation

Award Number: R01GM116897

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: 09/30/2015

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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