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Synaptonemal Complex Assembly and Function in Meiosis

Award Number: R01GM072551
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: 08/01/2005
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Synaptonemal Complex Assembly and Function in Meiosis - PROJECT SUMMARY Failure to achieve accurate chromosome segregation during meiosis is a leading cause of miscarriages, infertility, and birth defects such as Down syndrome. Therefore, understanding the mechanisms underlying accurate meiotic chromosome segregation is of paramount importance to human health. The synaptonemal complex (SC) is a zipper-like structure present from yeast to humans during meiosis that assembles between homologous chromosomes, stabilizing homologous pairing interactions and promoting interhomolog crossover formation. However, despite its importance for achieving accurate meiotic chromosome segregation, the mechanisms regulating chromosome synapsis and how the SC interfaces with recombination and chromosome remodeling is not well understood in any organism. Our goal is to identify mechanisms regulating the SC and to determine how SC regulation is linked to DNA double-strand break (DSB) repair progression and late prophase I chromosome remodeling to ensure accurate meiotic chromosome segregation. We study this in the nematode C. elegans because it shares a high degree of gene conservation with humans and affords ease of genetic, cytological, molecular, and biochemical analysis for germline studies. Our progress during the previous funding period, coupled with new data and molecular targets, place us in an ideal position to understand the regulation and roles of chromosome synapsis during meiosis. Here we propose two integrated aims to address these critical issues. Aim 1 will determine how HIM-22, a protein which shares sequence conservation with yeast Set3 and human ASH1L, regulates SC formation. HIM-22 promotes protein deacetylation in the germline, interacts with a structural component of the SC, and is required for regulating SC assembly, crossover levels, and late prophase I chromosome remodeling; this will define a previously unknown meiotic role for this protein modifier in a metazoan and a new mode of SC regulation. Aim 2 will determine how NatF-mediated N-terminal acetylation of meiotic proteins regulates the SC. Our studies show that NatF is required for protein acetylation in the germline, and regulates SC assembly/disassembly, DSB repair progression, crossover distribution, and late prophase I chromosome remodeling. We previously found that NatB-mediated N-terminal acetylation of a structural component of the SC promotes SC assembly. Our past studies on NatB and our current discovery of NatF as a potential regulator of the SC suggest there is a conserved yet poorly understood regulatory network of different N-acetyltransferases acting on chromosome synapsis. These studies will shed new light on our understanding of the mechanisms regulating chromosome synapsis and how these link the SC to DSB repair and late prophase I chromosome remodeling. Our studies will impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of post-translational modifications, and regulation of macromolecular structures. Taken together, this application will provide novel insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.


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 = $507,680 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	19	12/18/2024	NON-COMPETING CONTINUATION	$403,815
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	19	12/19/2024	SUPPLEMENT FOR EXPANSION	$103,865
														Subtotal = $507,680

Issue Date FY: 2024 ( Subtotal = $500,617 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	18	12/21/2023	COMPETING CONTINUATION	$448,683
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	003	18	6/12/2024	SUPPLEMENT FOR EXPANSION	$51,934
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	18	1/2/2024	COMPETING CONTINUATION	$21,853
2024	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	17	11/25/2023	NON-COMPETING CONTINUATION	-$21,853
														Subtotal = $500,617

Issue Date FY: 2023 ( Subtotal = -$18,166 )
2023	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	17	11/29/2022	SUPPLEMENT FOR EXPANSION	-$6,731
2023	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	16	11/29/2022	SUPPLEMENT FOR EXPANSION	-$11,435
														Subtotal = -$18,166

Issue Date FY: 2022 ( Subtotal = $405,898 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	17	7/30/2022	NON-COMPETING CONTINUATION	$399,167
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	17	7/31/2022	SUPPLEMENT FOR EXPANSION	$6,731
														Subtotal = $405,898

Issue Date FY: 2021 ( Subtotal = $473,022 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	16	7/30/2021	NON-COMPETING CONTINUATION	$399,167
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	003	16	9/8/2021	SUPPLEMENT FOR EXPANSION	$73,855
2021	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	14	10/13/2020	COMPETING CONTINUATION	$18,706
2021	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	13	10/13/2020	NON-COMPETING CONTINUATION	-$18,706
														Subtotal = $473,022

Issue Date FY: 2020 ( Subtotal = $399,167 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	15	7/20/2020	NON-COMPETING CONTINUATION	$399,167
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	14	5/5/2020	COMPETING CONTINUATION	$3,147
2020	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	13	5/5/2020	NON-COMPETING CONTINUATION	-$3,147
														Subtotal = $399,167

Issue Date FY: 2019 ( Subtotal = $416,785 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	14	9/19/2019	COMPETING CONTINUATION	$416,785
2019	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	13	9/19/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,785

Issue Date FY: 2018 ( Subtotal = $334,763 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	13	7/13/2018	NON-COMPETING CONTINUATION	$334,763
														Subtotal = $334,763

Issue Date FY: 2017 ( Subtotal = $334,763 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	12	7/26/2017	NON-COMPETING CONTINUATION	$334,763
														Subtotal = $334,763

Issue Date FY: 2016 ( Subtotal = $334,763 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	11	7/25/2016	NON-COMPETING CONTINUATION	$334,763
														Subtotal = $334,763

Issue Date FY: 2015 ( Subtotal = $334,763 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	10	7/17/2015	COMPETING CONTINUATION	$334,763
														Subtotal = $334,763

Issue Date FY: 2013 ( Subtotal = $327,912 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	9	7/30/2013	NON-COMPETING CONTINUATION	$327,912
														Subtotal = $327,912

Issue Date FY: 2012 ( Subtotal = $339,806 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	8	7/23/2012	NON-COMPETING CONTINUATION	$339,806
														Subtotal = $339,806

Issue Date FY: 2011 ( Subtotal = $339,806 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	7	7/21/2011	NON-COMPETING CONTINUATION	$339,806
														Subtotal = $339,806

Issue Date FY: 2010 ( Subtotal = $383,047 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	5	1/15/2010	SUPPLEMENT FOR EXPANSION	$39,809
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	6	7/23/2010	COMPETING CONTINUATION	$343,238
2010	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	5	7/22/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $383,047

Issue Date FY: 2009 ( Subtotal = $305,362 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	7/24/2009	NON-COMPETING CONTINUATION	$305,362
														Subtotal = $305,362

Issue Date FY: 2008 ( Subtotal = $305,362 )
2008	2008	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	7/18/2008	NON-COMPETING CONTINUATION	$305,362
														Subtotal = $305,362

Issue Date FY: 2007 ( Subtotal = $305,362 )
2007	2007	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	7/26/2007	NON-COMPETING CONTINUATION	$305,362
														Subtotal = $305,362

Grand Total All Awards = $6,967,244

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Synaptonemal Complex Assembly and Function in Meiosis

Award Number: R01GM072551

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: 08/01/2005

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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