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Structure and Function of a Eukaryotic Centromere

Award Number: R01GM032238
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: 07/01/1983
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Structure and Function of a Eukaryotic Centromere - Project Summary Goals: The centromere serves as the binding site for the kinetochore and is essential for the faithful segregation of chromosomes throughout cell division. The point centromere in yeast is encoded by a ~115 bp specific DNA sequence, whereas regional centromeres span 6-10 kbp in fission yeast to 5-10 Mbp in human. Despite the apparent diversity in centromere organization, the distance between sister kinetochores in metaphase ranges from 800 nm to 1,000 nm in yeast, worms, flies, flower moths, plants, horses and human. Understanding the physical structure of centromere chromatin (pericentromere in yeast, defined as the chromatin between sister kinetochores) will provide fundamental insights how centromere DNA is organized into a stiff spring that resists microtubule pulling forces during mitosis. Approach: Our laboratory develops computational tools to interrogate the structure and dynamics of hundreds of kilobase pairs of pericentromeric DNA. Together with experimentally obtained images of fluorescent probes of pericentromeric structure (e.g. pericentromere DNA, cohesin, condensin) we make quantitative comparisons between simulations and experimental results through transformation of in silico models into microscope images (model convolution). We will test the proposal that the mechanism for building tension between sister kinetochores is a chromatin bottlebrush organized by the loop-extruding proteins condensin and cohesin. The bottlebrush provides a biophysical mechanism that transforms pericentromeric chromatin into a spring due to the steric repulsion between radial loops. The bottlebrush as an organizing principle for chromosome organization has emerged from multiple approaches in the field. We will leverage the powerful features of chromosome engineering in yeast to explore the consequences of reducing the number of centromeres, and exploit synthetic bottlebrushes and statistical physics of polymer models to reveal basic principles linking bottlebrush structure to the functional readout of force/tension. Innovation: We will combine our experience in chromosome engineering and advanced bioimaging in yeast with the expertise of collaborators in statistical physics and applied math (Forest UNC-CH) and synthetic bio-inspired materials (Freeman UNC-CH). Testing our hypotheses will elucidate important information about the organization and function of centromeres, potentially providing a paradigm shifting foundation for the remarkable conservation of distance between sister kinetochores throughout phylogeny.


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 = $475,014 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	38	2/24/2025	NON-COMPETING CONTINUATION	$475,014
														Subtotal = $475,014

Issue Date FY: 2024 ( Subtotal = $527,794 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	37	2/27/2024	NON-COMPETING CONTINUATION	$475,014
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	37	7/15/2024	NON-COMPETING CONTINUATION	$52,780
														Subtotal = $527,794

Issue Date FY: 2023 ( Subtotal = $777,136 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	002	36	9/7/2023	SUPPLEMENT FOR EXPANSION	$248,643
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	36	2/24/2023	NON-COMPETING CONTINUATION	$528,218
2023	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	35	11/17/2022	COMPETING CONTINUATION	$275
														Subtotal = $777,136

Issue Date FY: 2022 ( Subtotal = $528,883 )
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	35	4/8/2022	COMPETING CONTINUATION	$528,883
														Subtotal = $528,883

Issue Date FY: 2011 ( Subtotal = $0 )
2011	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	000	24	8/1/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $466,717 )
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	23	5/26/2010	SUPPLEMENT FOR EXPANSION	$30,000
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	24	7/19/2010	NON-COMPETING CONTINUATION	$436,717
														Subtotal = $466,717

Issue Date FY: 2009 ( Subtotal = $485,997 )
2009	2009	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	001	23	9/30/2009	SUPPLEMENT FOR EXPANSION	$50,345
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	23	7/29/2009	NON-COMPETING CONTINUATION	$435,652
														Subtotal = $485,997

Issue Date FY: 2008 ( Subtotal = $423,104 )
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	22	7/31/2008	NON-COMPETING CONTINUATION	$423,104
														Subtotal = $423,104

Issue Date FY: 2007 ( Subtotal = $498,677 )
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	21	7/27/2007	COMPETING CONTINUATION	$498,677
														Subtotal = $498,677

Issue Date FY: 2006 ( Subtotal = $362,938 )
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	20	5/1/2006	NON-COMPETING CONTINUATION	$362,938
														Subtotal = $362,938

Issue Date FY: 2005 ( Subtotal = $361,366 )
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	19	4/27/2005	NON-COMPETING CONTINUATION	$361,366
														Subtotal = $361,366

Issue Date FY: 2004 ( Subtotal = $351,363 )
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	18	4/21/2004	NON-COMPETING CONTINUATION	$351,363
														Subtotal = $351,363

Issue Date FY: 2003 ( Subtotal = $391,467 )
2003	2003	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Cell Biology and Biophysics Research	000	17		COMPETING CONTINUATION	$391,467
														Subtotal = $391,467

Issue Date FY: 2001 ( Subtotal = $234,636 )
2001	2001	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	16	3/2/2001	NON-COMPETING CONTINUATION	$234,636
														Subtotal = $234,636

Issue Date FY: 2000 ( Subtotal = $227,938 )
2000	2000	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	15	2/16/2000	NON-COMPETING CONTINUATION	$227,938
														Subtotal = $227,938

Issue Date FY: 1999 ( Subtotal = $221,434 )
1999	1999	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	14	3/22/1999	NON-COMPETING CONTINUATION	$221,434
														Subtotal = $221,434

Issue Date FY: 1998 ( Subtotal = $291,320 )
1998	1998	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	13	3/12/1998	COMPETING CONTINUATION	$291,320
														Subtotal = $291,320

Grand Total All Awards = $6,625,784

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Structure and Function of a Eukaryotic Centromere

Award Number: R01GM032238

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: 07/01/1983

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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