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Mechanisms of Kinetochore Assembly

Award Number: R01GM074728
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: 09/01/2005
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Mechanisms of Kinetochore Assembly - Project Summary The process of cell division requires that each cell receive an identical complement of the genome. Errors in chromosome segregation give rise to chromosomal aneuploidies that are causative for human genetic disease such as Down syndrome and promote the progression of most human cancers. The work in this proposal is focused on understanding the functions of the centromere and kinetochore, the primary site on the chromosome that attaches each chromosome to the mitotic spindle for proper segregation during division. The centromere and kinetochore serve as the primary control center for chromosome segregation through their roles in microtubule attachment, force coupling for chromosome movement, and error correction when chromosome attachment or alignment on microtubules is perturbed. Underlying the centromere is a specialized chromatin domain that is delineated by replacement of histone H3 in nucleosomes with a centromere specific histone variant termed CENP-A. The position of CENP-A defines where the centromere and kinetochore will form and defects in CENP-A assembly or maintenance cause centromere and kinetochore loss which result in chromosome missegregation. In this proposal we study three different aspects of CENP-A chromatin. In our first Aim we work to understand how the assembly of CENP-A chromatin is controlled so that the centromere is replenished during each cell cycle and maintained through replication and cell division. We focus on three important factors for CENP-A assembly, CENP-C, HJURP and the Mis18 complex that are essential for building new CENP-A nucleosomes at centromeres. Our second aim studies the problem of how the presence of CENP-A in chromatin dictates the sites of new CENP-A assembly. We apply a new method we have developed called DiMeLo-seq that overcomes existing limitations in studying the complex repetitive centromeres of vertebrates. This approach uses directed methylation to mark the sites where proteins are bound to chromatin and then uses long read sequencing to map the binding sites through the repetitive centromere sequences. We use this approach to study the density, distribution, and sites of regeneration of CENP-A through the cell cycle. In our third aim we study how centromeres are condensed and organized by the activities of CENP-A nucleosome binding proteins. We discovered that two centromere proteins (CENP-C and CENP-N) can bridge CENP-A nucleosomes and condense centromeric chromatin. We use human cells to test the role of this condensation activity in centromere condensation, resistance to force, and chromosome segregation. Overall, our proposal will elucidate the regulatory mechanisms and structural organization of vertebrate centromeres and how those properties ensure accurate chromosome segregation.


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 = $334,123 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	003	19	5/16/2025	NON-COMPETING CONTINUATION	$33,412
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	19	12/13/2024	NON-COMPETING CONTINUATION	$300,711
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	18	1/15/2025	COMPETING CONTINUATION	$0
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	17	1/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $334,123

Issue Date FY: 2024 ( Subtotal = $370,123 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	18	9/4/2024	SUPPLEMENT FOR EXPANSION	$36,000
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	18	12/19/2023	COMPETING CONTINUATION	$334,123
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	17	12/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,123

Issue Date FY: 2022 ( Subtotal = $332,971 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	17	2/4/2022	NON-COMPETING CONTINUATION	$299,673
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	17	7/27/2022	NON-COMPETING CONTINUATION	$33,298
														Subtotal = $332,971

Issue Date FY: 2021 ( Subtotal = $541,651 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	16	2/12/2021	NON-COMPETING CONTINUATION	$331,390
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	16	8/3/2021	SUPPLEMENT FOR EXPANSION	$210,261
														Subtotal = $541,651

Issue Date FY: 2020 ( Subtotal = $329,343 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	15	2/19/2020	NON-COMPETING CONTINUATION	$329,343
														Subtotal = $329,343

Issue Date FY: 2019 ( Subtotal = $327,356 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	14	4/1/2019	COMPETING CONTINUATION	$327,356
2019	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	13	3/27/2019	NON-COMPETING CONTINUATION	$0
2019	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	13	7/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $327,356

Issue Date FY: 2017 ( Subtotal = $332,876 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	13	8/28/2017	NON-COMPETING CONTINUATION	$332,876
														Subtotal = $332,876

Issue Date FY: 2016 ( Subtotal = $332,627 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	12	9/13/2016	NON-COMPETING CONTINUATION	$332,627
														Subtotal = $332,627

Issue Date FY: 2015 ( Subtotal = $332,395 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	11	7/27/2015	NON-COMPETING CONTINUATION	$332,395
														Subtotal = $332,395

Issue Date FY: 2014 ( Subtotal = $332,180 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	10	8/20/2014	COMPETING CONTINUATION	$332,180
														Subtotal = $332,180

Issue Date FY: 2013 ( Subtotal = $314,976 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	9	8/28/2013	NON-COMPETING CONTINUATION	$314,976
														Subtotal = $314,976

Issue Date FY: 2012 ( Subtotal = $325,737 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	8	8/24/2012	NON-COMPETING CONTINUATION	$325,737
														Subtotal = $325,737

Issue Date FY: 2011 ( Subtotal = $325,099 )
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	7	8/22/2011	NON-COMPETING CONTINUATION	$325,099
														Subtotal = $325,099

Issue Date FY: 2010 ( Subtotal = $413,611 )
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	6	8/27/2010	COMPETING CONTINUATION	$327,760
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Recovery Act Research Support	000	5	1/8/2010	SUPPLEMENT FOR EXPANSION	$85,851
														Subtotal = $413,611

Issue Date FY: 2009 ( Subtotal = $253,404 )
2009	2009	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	8/11/2009	NON-COMPETING CONTINUATION	$253,404
														Subtotal = $253,404

Issue Date FY: 2008 ( Subtotal = $253,404 )
2008	2008	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	8/21/2008	NON-COMPETING CONTINUATION	$253,404
														Subtotal = $253,404

Issue Date FY: 2007 ( Subtotal = $253,404 )
2007	2007	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	8/29/2007	NON-COMPETING CONTINUATION	$253,404
														Subtotal = $253,404

Issue Date FY: 2006 ( Subtotal = $260,972 )
2006	2006	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	8/7/2006	NON-COMPETING CONTINUATION	$260,972
														Subtotal = $260,972

Issue Date FY: 2005 ( Subtotal = $287,708 )
2005	2005	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	8/4/2005	NEW	$287,708
														Subtotal = $287,708

Grand Total All Awards = $6,253,960

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Mechanisms of Kinetochore Assembly

Award Number: R01GM074728

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: 09/01/2005

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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