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How Does a Synaptonemal Complex Protein Promote Crossover Recombination and Synapsis?

Award Number: R15GM116109
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: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 09/01/2028

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How Does a Synaptonemal Complex Protein Promote Crossover Recombination and Synapsis? - Project Summary Our proposed research aims to decipher the molecular mechanisms that underlie homologous chromosome segregation during reproductive cell formation. Meiosis is the specialized cell division cycle that partitions the two homologous copies of every chromosome (homologs) to separate daughter nuclei, effectively reducing chromosome ploidy. Errors in chromosome segregation lead to aneuploid reproductive cells carrying too many or two few chromosomes. Key to successful homolog segregation is the prior establishment of transient but stable linkages between replicated chromosomes; for most organisms these links are formed by interhomolog crossover recombination events, in conjunction with intact sister cohesion. How crossover events are efficiently generated between every chromosome pair during meiosis remains poorly understood, but for most organisms it is clear the process involves an exquisite coordination between large-scale chromosome movements and local DNA repair processes. A conserved multi-protein structure, the synaptonemal complex (SC), mediates an intimate alignment between homologous partner chromosome axes and forms the physical context in which DNA repair intermediates undergo maturation. SC has long been associated with successful crossover recombination, and although our research demonstrated that the SC structure per se is dispensable for crossing over in S. cerevisiae (budding yeast), we also showed that the SC structural component, Zip1, has a genetically separable function in promoting crossovers. Our structurefunction analysis reveals adjacent domains within Zip1 's N terminus that function independently to promote crossover recombination and SC assembly, potentially through separate but adjacent interactions with the procrossover E3 SUMO ligase, Zip3, and the SC central element protein complex Ecm11-Gmc2. Our research over the past two years has i) obtained additional evidence for an intriguing phosphorylationbased switch mechanism that controls Zip1's crossover and SC assembly activities, ii) revealed noncontiguous regions of Zip1 that phenocopy one another in a manner that suggests a specific overlapping configuration of Zip1 within mature SC, iii) discovered Zip1 protects Zip3 from proteosome-mediated degradation, iv) corrected Zip3's translational start site, and v) developed proximity labeling as a tool to both study interactions between pro-crossover and SC proteins and to identify new proximity targets of crossover and synapsis proteins. Experiments proposed in this renewal application support a rich training environment for one doctoral student and several undergraduates and use a cost-effective organism with powerful molecular genetics accessible to students at all levels. The proposed Aims build upon recent data and are designed to deepen our understanding of how Zip1 's N terminus collaborates with other factors, particularly the Zip3 SUMO ligase, to promote crossover recombination, and how Zip1 's pro-crossover activity is properly coordinated with and coupled to assembly of the supramolecular SC structure, which also requires Zip1 as a building block.


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 = $598,500 )
2025	2025	WESLEYAN UNIVERSITY	237 HIGH ST	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	4	9/2/2025	COMPETING CONTINUATION	$598,500
														Subtotal = $598,500

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	WESLEYAN UNIVERSITY	237 HIGH ST	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	001	3	11/9/2022	COMPETING CONTINUATION	$1,930
2023	2019	WESLEYAN UNIVERSITY	237 HIGH ST	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	2	11/9/2022	COMPETING CONTINUATION	-$1,930
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $492,900 )
2022	2022	WESLEYAN UNIVERSITY	237 HIGH STREET RM 409	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	001	3	8/1/2022	COMPETING CONTINUATION	$492,900
2022	2019	WESLEYAN UNIVERSITY	237 HIGH STREET RM 409	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	2	7/31/2022	COMPETING CONTINUATION	$0
														Subtotal = $492,900

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	WESLEYAN UNIVERSITY	237 HIGH STREET RM 409	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	1	1/26/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $492,900 )
2019	2019	WESLEYAN UNIVERSITY	237 HIGH STREET RM 409	MIDDLETOWN	CT	06459	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	2	8/7/2019	COMPETING CONTINUATION	$492,900
														Subtotal = $492,900

Issue Date FY: 2016 ( Subtotal = $492,900 )
2016	2016	WESLEYAN UNIVERSITY	186 College St	MIDDLETOWN	CT	06457	LOWER CT RIVER VLY	USA	Biomedical Research and Research Training	000	1	7/25/2016	NEW	$492,900
														Subtotal = $492,900

Grand Total All Awards = $2,077,200

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How Does a Synaptonemal Complex Protein Promote Crossover Recombination and Synapsis?

Award Number: R15GM116109

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: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 09/01/2028

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