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Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents

Award Number: R01GM126363
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: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents - Type II topoisomerases are ubiquitous enzymes that are required for proper chromosome structure and segregation and play important roles in DNA replication, transcription, and recombination. These enzymes relax DNA and remove knots and tangles from the genetic material by passing an intact double helix (transport segment) through a transient double-stranded break that they generate in a separate DNA segment (gate segment). Humans encode two closely related isoforms of the type II enzyme, topoisomerase IIα and topoisomerase IIβ. Topoisomerase IIα is essential for the survival of proliferating cells and topoisomerase IIβ plays critical roles during development. However, because these enzymes generate requisite double-stranded DNA breaks during their crucial catalytic functions, they assume a dual persona. Although essential to cell survival, they also pose an intrinsic threat to genomic integrity every time they act. Beyond their critical physiological functions, topoisomerase IIα and IIβ are the primary targets for some of the most active and widely prescribed drugs currently used for the treatment of human cancers. These agents kill cells by stabilizing covalent topoisomerase II-cleaved DNA complexes (cleavage complexes) that are normal, but fleeting, intermediates in the catalytic DNA strand passage reaction. When the resulting enzyme- associated DNA breaks are present in sufficient concentrations, they can trigger cell death pathways. Anticancer drugs that target type II enzymes are referred to as topoisomerase II poisons because they convert these indispensable enzymes to potent physiological toxins that generate DNA damage in treated cells. Although topoisomerase IIα and IIβ are important targets for cancer chemotherapy, they also have the potential to trigger specific leukemias. For example, a small percentage of patients with cancer or multiple sclerosis who are treated with the topoisomerase II-targeted drug mitoxantrone go on to develop acute promyelocytic leukemias (APLs) with 15:17 translocations. Despite the importance of type II topoisomerases in cell growth and cancer, we still have much to learn about how the human enzymes function and interact with DNA and anticancer drugs. Thus, this proposal will further define the catalytic mechanism of type II topoisomerases and examine how enzyme activity is regulated in the cell. It also will define mechanisms by which established and novel topoisomerase II-targeted agents, environ- mental chemicals, and natural products increase levels of enzyme-mediated DNA breaks or inhibit enzyme activity and determine the cellular consequences of topoisomerase II poisons. The primary research models for this study will be human topoisomerase IIα and IIβ, cultured human cells, and Xenopus laevis egg extracts. Gyrase and topoisomerase IV from Escherichia coli and Bacillus anthracis will be used as counterpoints to mechanistic experiments and Mycobacterium tuberculosis gyrase will be used to assess relationships between the mechanisms of action of drugs targeted to prokaryotic and eukaryotic type II enzymes.


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 = $320,181 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	8	11/27/2024	NON-COMPETING CONTINUATION	$320,181
														Subtotal = $320,181

Issue Date FY: 2024 ( Subtotal = $355,756 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	7	6/11/2024	NON-COMPETING CONTINUATION	$35,575
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	7	11/9/2023	NON-COMPETING CONTINUATION	$320,181
														Subtotal = $355,756

Issue Date FY: 2023 ( Subtotal = $355,756 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	003	6	2/15/2023	NON-COMPETING CONTINUATION	$35,575
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	6	11/17/2022	NON-COMPETING CONTINUATION	$320,181
2023	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	5	2/10/2023	COMPETING CONTINUATION	$33,823
2023	2021	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	4	2/10/2023	NON-COMPETING CONTINUATION	-$33,823
														Subtotal = $355,756

Issue Date FY: 2022 ( Subtotal = $355,756 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	5	12/1/2021	COMPETING CONTINUATION	$355,756
2022	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	4	11/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $355,756

Issue Date FY: 2021 ( Subtotal = $302,225 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	4	11/20/2020	NON-COMPETING CONTINUATION	$272,002
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	4	2/11/2021	NON-COMPETING CONTINUATION	$30,223
														Subtotal = $302,225

Issue Date FY: 2020 ( Subtotal = $302,225 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	3	3/5/2020	NON-COMPETING CONTINUATION	$30,223
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	3	1/3/2020	NON-COMPETING CONTINUATION	$272,002
														Subtotal = $302,225

Issue Date FY: 2019 ( Subtotal = $302,225 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	2	1/16/2019	NON-COMPETING CONTINUATION	$302,225
														Subtotal = $302,225

Issue Date FY: 2018 ( Subtotal = $302,225 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	1	1/24/2018	NEW	$302,225
														Subtotal = $302,225

Grand Total All Awards = $2,596,349

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Mechanistic Studies of Type II Topoisomerases and Topoisomerase-Targeted Agents

Award Number: R01GM126363

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: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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