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Understanding the reciprocal regulation between Hsp70 and the DNA damage response

Award Number: R01GM139885
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: 12/03/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Understanding the reciprocal regulation between Hsp70 and the DNA damage response - Project Summary All organisms require maintenance of DNA integrity to grow and proliferate. Replication and repair of DNA damage requires the increased synthesis of DNA nucleotides, a process that is dependent on the activity of the kinases such as ATM and ATR. Misregulation of DNA replication can result in either cell death or cancer. Studies by our lab and others have shown that many DNA damage response (DDR) proteins (such as ATM, ATR, XRCC1 and RNR) are stabilized by the molecular chaperones Hsp70 and Hsp90. These proteins perform a variety of functions in the cell including protein folding of both newly synthesized and denatured proteins, protein transport across membranes and disaggregation of oligomerized proteins. Research has primarily focused on how chaperone function specificity arises through regulation of expression, isoform differences and the variety of co- chaperone proteins that bind to the Hsp70 and Hsp90 molecules. Despite the identification of several phosphorylation sites on both yeast and mammalian Hsp70 through global proteomic screens (known as the chaperone code), the biological function of these remains unclear. Our studies published in Cell determined that CDK-mediated phosphorylation of a single site on Hsp70 can regulate chaperone function by altering both co- chaperone and client protein interactions. In this proposal, we aim to understand how the activation of DDR can promote changes in the pattern of Hsp70 chaperone code. We predict that in line with several Hsp90-kinase interactions, Hsp70 phosphorylation during DNA damage creates a feedback system whereby chaperone phosphorylation increases stability of DDR proteins, amplifying the signal of the DNA damage response. We propose to use both molecular biology and state-of-the-art mass spectrometric techniques on both Saccharomyces cerevisiae and mammalian cell culture cells to achieve the aims of the objectives in our proposal. Identification and study of functional phosphorylation sites on Hsp70 in both yeast and mammalian cells will provide us with a completely novel way to target chaperone activity. Hsp70 activity may be suppressed using specific phosphatase/kinase inhibitors. It may be possible to target specific ‘client’ proteins though alteration of Hsp70 phosphorylation status and specific Hsp70 phospho-species may have a higher susceptibility to inhibitors. The scope of this work has broad implications for a variety of diseases associated with both the DNA damage response and molecular chaperone function, including many types of cancer and neurodegenerative illnesses caused by protein aggregation (Huntington’s disease, Alzheimer’s disease and Creutzfeld-Jakob disease).


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	2024	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	000	4	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $294,296 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	001	4	6/18/2024	NON-COMPETING CONTINUATION	$29,429
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	000	4	12/18/2023	NON-COMPETING CONTINUATION	$264,867
														Subtotal = $294,296

Issue Date FY: 2023 ( Subtotal = $385,583 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	002	3	3/31/2023	NON-COMPETING CONTINUATION	$29,470
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	001	3	12/2/2022	SUPPLEMENT FOR EXPANSION	$53,175
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	003	3	6/20/2023	SUPPLEMENT FOR EXPANSION	$37,710
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	000	3	12/1/2022	NON-COMPETING CONTINUATION	$265,228
														Subtotal = $385,583

Issue Date FY: 2022 ( Subtotal = $405,879 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	003	2	8/26/2022	SUPPLEMENT FOR EXPANSION	$15,799
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	000	2	11/25/2021	NON-COMPETING CONTINUATION	$265,570
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	002	2	8/3/2022	NON-COMPETING CONTINUATION	$29,508
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	001	2	6/21/2022	SUPPLEMENT FOR EXPANSION	$95,002
														Subtotal = $405,879

Issue Date FY: 2021 ( Subtotal = $295,439 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	12/3/2020	NEW	$295,439
														Subtotal = $295,439

Grand Total All Awards = $1,381,197

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Understanding the reciprocal regulation between Hsp70 and the DNA damage response

Award Number: R01GM139885

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: 12/03/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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