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Control of Chromosome Segregation by DNA Topoisomerase II

Award Number: R01GM130858
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Control of Chromosome Segregation by DNA Topoisomerase II - Title: Control of Chromosome Segregation by DNA Topoisomerase II. Abstract Chromosome segregation errors result in aneuploidy, which causes birth defects and cancer. We have defined a new mitotic Topo II-responsive control (TRC) that delays the cell cycle when Topo II activity is insufficient for accurate chromosome segregation. This TRC mechanism is conserved from yeast to human cells but has not been extensively studied. Activation of the TRC is triggered by stalling of the strand passage reaction of Topo II, when the enzyme becomes trapped on DNA in the Closed Clamp structural conformation. TRC activation requires two distinct modules within the catalytically inert C-terminal domain of TopoII: (i) A cluster of SUMOylation sites, and (ii) The Chromatin Tether domain of Topo II, which interacts with methylated nucleosomes. The central molecular model is that stalled strand passage leads to C-terminal domain SUMOylation that functions as a signal-generating scaffold to halt the cell cycle. The conservation between the human and yeast TRC responses provided unique opportunities to identify TRC components, but gaps remain in our understanding of the mechanism of TRC activation. We aim to determine how the TRC activates Mad2 to inhibit anaphase initiation, which will require determining the identity of the E3 ligase that SUMOylates TopoII as well as the relevant substrates of Aurora B kinase. We will determine how trapped Closed Clamps trigger TopoII SUMOylation and how they are repaired. The role of the ChT domain will be determined and whether interaction with nucleosomes is required for TRC activation. The results of these studies will impact opportunities for translational research because we will identify new potential therapeutic targets. Our findings will also impact the use of widely prescribed therapeutic drugs that target Topo II because we will gain mechanistic insight into cellular responses to Topo II inhibition. The preliminary data and newly developed experimental tools place us in a unique position to determine the conserved mechanism of this scarcely studied mitotic control.


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 = $304,045 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	002	6	8/12/2025	NON-COMPETING CONTINUATION	$30,403
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	6	2/26/2025	NON-COMPETING CONTINUATION	$273,642
2025	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	4	1/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $304,045

Issue Date FY: 2024 ( Subtotal = $317,795 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	3/25/2024	COMPETING CONTINUATION	$317,795
														Subtotal = $317,795

Issue Date FY: 2022 ( Subtotal = $292,937 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	4	7/26/2022	NON-COMPETING CONTINUATION	$29,295
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	4	12/8/2021	NON-COMPETING CONTINUATION	$263,642
														Subtotal = $292,937

Issue Date FY: 2021 ( Subtotal = $292,871 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	1/5/2021	NON-COMPETING CONTINUATION	$263,583
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	3	3/19/2021	NON-COMPETING CONTINUATION	$29,288
														Subtotal = $292,871

Issue Date FY: 2020 ( Subtotal = $292,808 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	1/14/2020	NON-COMPETING CONTINUATION	$292,808
														Subtotal = $292,808

Issue Date FY: 2019 ( Subtotal = $425,882 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	1	8/5/2019	SUPPLEMENT FOR EXPANSION	$122,738
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	2/27/2019	NEW	$303,144
														Subtotal = $425,882

Grand Total All Awards = $1,926,338

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Control of Chromosome Segregation by DNA Topoisomerase II

Award Number: R01GM130858

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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