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Investigation of the physiological significance of protein acetylation in Bacillus subtilis

Award Number: R35GM138303
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Investigation of the physiological significance of protein acetylation in Bacillus subtilis - ABSTRACT Until recently, N-lysine acetylation was thought to be rare in bacteria, but is now appreciated to affect hundreds of bacterial proteins with diverse cellular functions. Acetylation was initially discovered as a post-translational modification (PTM) on the unstructured, highly basic N-terminal tails of eukaryotic histones. Histone acetylation constitutes part of the “histone code,” and regulates chromosome compaction and various DNA processes, such as gene expression, replication, repair and recombination. In eukaryotes, acetylation regulates many other proteins in addition to histones, involved in a wide array of important biological processes. This observation is also true in bacteria, as evidenced by the characterization of the acetylomes of more than 30 different bacterial species. However, the physiological significance of the vast majority of these modifications remains unknown. In addition, the mechanisms of acetylation and deacetylation, and the bacterial enzymes involved are not completely understood. To address these gaps in knowledge, we have focused on studying the acetylation of the essential, histone-like protein HBsu in Bacillus subtilis. In bacteria, the nucleoid is compacted and organized by the action of nucleoid-associated proteins (NAPs). HBsu is a member of the most widely conserved NAP family, and is considered a functional equivalent of eukaryotic histones. We found that HBsu contains seven novel acetylation sites, and this raised the exciting possibility that these modifications represent a “histone-like” code in bacteria. So far, we discovered that acetylation of HBsu at key lysine residues is required to maintain normal chromosome compaction. Additionally, we identified the second protein acetyltransferase in B. subtilis. The overall goal of our research program is to decipher this code. Our recent progress supports the hypotheses that acetylation of HBsu regulates cell division and sporulation, and that there are additional enzymes involved in regulating acetylation. The short- term goals of this work are to define the enzymatic mechanism of regulation of HBsu acetylation and determine the significance of HBsu acetylation in the regulation of DNA transactions, stationary phase development and drug tolerance. Additionally, we will develop new biochemical and mass-spectrometry based proteomics techniques for the study of acetylation in bacteria. Our long-term goals are to characterize additional HBsu PTMs, identify and characterize novel enzymes of acetylation, and perform a detailed structural and biochemical analysis with acetylated HBsu and novel enzymes. Ultimately, we will design novel inhibitors of bacterial acetylation enzymes or acetylated HBsu and assess their efficacy as potential novel antimicrobial therapies. Together, these studies may demonstrate the existence of a histone- like code in bacteria, an unexpected and exciting new field of biology. Furthermore, these studies will provide the foundation for designing novel antimicrobial drugs that target protein acetylation, either the enzymes or key acetylated targets.


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	ROWAN UNIVERSITY	201 MULLICA HILL RD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	5	7/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $365,086 )
2024	2024	ROWAN UNIVERSITY	201 MULLICA HILL RD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	5	6/7/2024	NON-COMPETING CONTINUATION	$365,086
														Subtotal = $365,086

Issue Date FY: 2023 ( Subtotal = $424,097 )
2023	2023	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	001	4	6/28/2023	NON-COMPETING CONTINUATION	$0
2023	2023	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	4	6/22/2023	NON-COMPETING CONTINUATION	$365,391
2023	2023	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	002	4	6/28/2023	SUPPLEMENT FOR EXPANSION	$58,706
														Subtotal = $424,097

Issue Date FY: 2022 ( Subtotal = $365,391 )
2022	2022	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	3	7/4/2022	NON-COMPETING CONTINUATION	$365,391
														Subtotal = $365,391

Issue Date FY: 2021 ( Subtotal = $357,768 )
2021	2021	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	001	2	6/22/2021	NON-COMPETING CONTINUATION	$357,768
2021	2020	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	1	6/22/2021	NEW	$0
														Subtotal = $357,768

Issue Date FY: 2020 ( Subtotal = $396,314 )
2020	2020	ROWAN UNIVERSITY	201 MULLICA HILL RD RT 322	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	1	8/26/2020	NEW	$396,314
														Subtotal = $396,314

Grand Total All Awards = $1,908,656

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Investigation of the physiological significance of protein acetylation in Bacillus subtilis

Award Number: R35GM138303

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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