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Control of Histone mRNA Levels

Award Number: R01GM029832
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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ABSTRACT Animal replication-dependent histone mRNAs are the only eukaryotic mRNAs that lack a polyA tail ending instead in a conserved stemloop. In contrast mRNAs for histone variants, e.g. H3.3 and H2A.Z, are encoded by polyadenylated mRNAs. The genes for all five histone proteins are clustered in metazoan genomes, and factors required for histone gene expression are concentrated near the histone genes. A nuclear body, the histone locus body (HLB) forms at the histone genes and contains factors essential for histone mRNA biosynthesis. Our goal is to understand the detailed mechanisms unique to histone mRNA metabolism and regulation, which occurs primarily at the posttranscriptional level, both regulating histone pre-mRNA processing and histone mRNA degradation. The stemloop is the major cis element responsible for both these regulatory steps in the cell cycle regulation of histone mRNAs. The three aims of this proposal are: 1. Using an in vitro processing system composed primarily of recombinant proteins and synthetic RNAs to understand how the histone pre-mRNA is cleaved by a set of factors also used in cleavage and polyadenylation. These factors specifically assemble on the U7 snRNP. In particular we will determine the specific interactions between the U7 snRNP, the substrate and SLBP which activate the endonuclease CPSF73 for cleavage. 2. Understand the biochemical details, including the mechanism of regulation, of the novel pathway of histone mRNA degradation. Using CRISPR-Cas9 to edit the factors required for degradation, we will determine the mechanism by which the uridyl transferase TUT7 is recruited to modify histone mRNA, and the role of Upf1 in this process. 3. Understand how histone mRNA expression is regulated by factors present in the HLB, focusing on the changes that occur as cells progress from G1 to S-phase. NPAT, the major scaffolding factor, and FLASH, the factor required for assembly of the active U7 snRNP, are large, largely unstructured proteins, that contain small domains that interact with specific factors. We are characterizing the factors that interact with these proteins to determine factors involved in coordinate regulation of histone gene expression.


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: 2022 ( Subtotal = $449,174 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	47	5/12/2022	NON-COMPETING CONTINUATION	$449,174
														Subtotal = $449,174

Issue Date FY: 2021 ( Subtotal = $449,174 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	46	5/10/2021	NON-COMPETING CONTINUATION	$449,174
														Subtotal = $449,174

Issue Date FY: 2020 ( Subtotal = $533,214 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	003	45	7/29/2020	SUPPLEMENT FOR EXPANSION	$84,040
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	002	45	5/22/2020	NON-COMPETING CONTINUATION	$449,174
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	44	2/23/2020	COMPETING CONTINUATION	$2
2020	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	43	2/23/2020	SUPPLEMENT FOR EXPANSION	-$2
														Subtotal = $533,214

Issue Date FY: 2019 ( Subtotal = $449,174 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	44	8/6/2019	COMPETING CONTINUATION	$449,174
														Subtotal = $449,174

Issue Date FY: 2018 ( Subtotal = $455,546 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	43	9/6/2018	SUPPLEMENT FOR EXPANSION	$31,600
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	43	5/17/2018	NON-COMPETING CONTINUATION	$423,946
														Subtotal = $455,546

Issue Date FY: 2017 ( Subtotal = $474,633 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	42	5/29/2017	NON-COMPETING CONTINUATION	$474,633
														Subtotal = $474,633

Issue Date FY: 2016 ( Subtotal = $464,494 )
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	41	5/24/2016	NON-COMPETING CONTINUATION	$413,808
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	41	7/29/2016	SUPPLEMENT FOR EXPANSION	$50,686
														Subtotal = $464,494

Issue Date FY: 2015 ( Subtotal = $413,808 )
2015	2015	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	40	6/30/2015	COMPETING CONTINUATION	$413,808
														Subtotal = $413,808

Issue Date FY: 2014 ( Subtotal = $390,488 )
2014	2014	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	39	5/19/2014	NON-COMPETING CONTINUATION	$390,488
														Subtotal = $390,488

Issue Date FY: 2013 ( Subtotal = $376,826 )
2013	2013	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	38	5/21/2013	NON-COMPETING CONTINUATION	$376,826
														Subtotal = $376,826

Issue Date FY: 2012 ( Subtotal = $390,497 )
2012	2012	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	37	6/1/2012	NON-COMPETING CONTINUATION	$390,497
														Subtotal = $390,497

Issue Date FY: 2011 ( Subtotal = $390,502 )
2011	2011	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	36	5/27/2011	COMPETING CONTINUATION	$390,502
														Subtotal = $390,502

Issue Date FY: 2010 ( Subtotal = $466,005 )
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	35	5/17/2010	NON-COMPETING CONTINUATION	$364,872
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Trans-NIH Recovery Act Research Support	000	34	12/4/2009	SUPPLEMENT FOR EXPANSION	$101,133
														Subtotal = $466,005

Issue Date FY: 2009 ( Subtotal = $359,516 )
2009	2009	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	34	4/30/2009	NON-COMPETING CONTINUATION	$359,516
														Subtotal = $359,516

Issue Date FY: 2008 ( Subtotal = $350,706 )
2008	2008	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	33	5/12/2008	NON-COMPETING CONTINUATION	$350,706
														Subtotal = $350,706

Issue Date FY: 2007 ( Subtotal = $352,337 )
2007	2007	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	32	7/16/2007	COMPETING CONTINUATION	$352,337
														Subtotal = $352,337

Issue Date FY: 2006 ( Subtotal = $319,020 )
2006	2006	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	31	6/26/2006	NON-COMPETING CONTINUATION	$319,020
														Subtotal = $319,020

Issue Date FY: 2005 ( Subtotal = $326,697 )
2005	2005	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	30	6/24/2005	NON-COMPETING CONTINUATION	$326,697
														Subtotal = $326,697

Issue Date FY: 2004 ( Subtotal = $326,697 )
2004	2004	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	29	6/16/2004	NON-COMPETING CONTINUATION	$326,697
														Subtotal = $326,697

Issue Date FY: 2003 ( Subtotal = $326,697 )
2003	2003	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Genetics and Developmental Biology Research and Research Training	000	28	6/12/2003	COMPETING CONTINUATION	$326,697
														Subtotal = $326,697

Issue Date FY: 2002 ( Subtotal = $351,862 )
2002	2002	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Genetics and Developmental Biology Research and Research Training	000	27	6/6/2002	NON-COMPETING CONTINUATION	$283,626
2002	2002	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Genetics and Developmental Biology Research and Research Training	001	27	9/6/2002	SUPPLEMENT FOR EXPANSION	$68,236
														Subtotal = $351,862

Issue Date FY: 2001 ( Subtotal = $276,726 ) (Continued on the next page)
Grand Total All Awards = $9,449,459

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Control of Histone mRNA Levels

Award Number: R01GM029832

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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