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Regulation of MutL-gamma function in mediating crossing over in mammalian meiosis

Award Number: R01HD041012
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2003
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Regulation of MutL-gamma function in mediating crossing over in mammalian meiosis - During prophase I of meiosis, homologous recombination (HR) is initiated by the formation of hundreds of DNA double strand breaks (DSBs), leading to the formation of crossovers (CO) that are essential for maintaining chromosome interactions until the first meiotic division. In mouse, less than 10% of DSBs become COs, but the placement and timing of these events must be orchestrated with exact fidelity before the cell cycle can commence. Critical to this is the sequential loading of two heterodimers required for CO formation: MutSg (MSH4/MSH5) loads early onto ~150 DSBs, followed by MutLg (MLH1/MLH3) which is recruited to ~23 of these MutSg-licensed sites. The PI’s lab has been a central player in elucidating the roles of MutSg and MutLg in designating a CO fate in mammals, and we recently determined that Cyclin N-terminal Domain- containing-1 (CNTD1) is essential for paring down MutSg sites and loading MutLg to generate precise CO numbers. Unexpectedly, we find that mammalian CNTD1 does not act as a cyclin, and instead executes its functions by recruiting two major complexes. The first is Replication Factor C (RFC) which loads two clamps onto DNA (PCNA and 9-1-1). In somatic cells, PCNA activates MLH1, while 9-1-1 is an essential checkpoint regulator in mouse meiosis. The second complex is the SKP1-Cullin 1-Fbox complex (SCF), a ubiquitin E3 ligase whose major target is WEE1, which inactivates CDK1 and CDK2 through phosphorylation. Phosphorylation of CDK1 prevents metaphase I progression by inactivating Maturation Promoting Factor. We hypothesize that the CNTD1 acts as a surveillance mechanism to monitor CO designation and maturation through its interactions with RFC, and then to promote cell cycle progression through its interactions with SCF, but only once CO formation is assured. Three aims are proposed: (1) to elucidate the mechanism by which CNTD1 regulates the choice and usage of RFC clamp loaders and the PCNA/9-1-1 clamps to orchestrate class I CO designation and maturation. We will elucidate the role of RFC, PCNA, and other clamp/clamp loader combinations in promoting CO and checkpoint control downstream of CNTD1. (2) To explore the CNTD1-dependent role of the SCF in class I CO regulation and cell cycle progression. Studies in this aim will determine the components of the meiotic SCF, how CNTD1 regulates SCF through its interactions in the cytoplasm, and how CNTD1/SCF regulates cell cycle progression. (3) To understand the spatial and functional requirements for CNTD1 in mammalian meiosis. In silico analysis suggests variable use of the cyclin domain of CNTD1 across eukaryotes, suggesting that CNTD1 can function in two distinct ways to facilitate prophase I progression (as a cyclin, recruiting CDKs, or as a regulator of RFC and SCF). We will explore this dual activity by driving expression of either form in the mouse. Additional studies will investigate the distribution and movement of CNTD1 between cellular compartments during prophase I. These genetic approaches will elucidate how the mammalian CNTD1 protein functions to orchestrate CO designation during prophase.


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 = $601,091 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	22	8/8/2025	COMPETING CONTINUATION	$601,091
														Subtotal = $601,091

Issue Date FY: 2023 ( Subtotal = $436,026 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	21	5/18/2023	NON-COMPETING CONTINUATION	$436,026
														Subtotal = $436,026

Issue Date FY: 2022 ( Subtotal = $430,003 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	20	5/24/2022	NON-COMPETING CONTINUATION	$430,003
														Subtotal = $430,003

Issue Date FY: 2021 ( Subtotal = $424,526 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	19	5/28/2021	NON-COMPETING CONTINUATION	$424,526
														Subtotal = $424,526

Issue Date FY: 2020 ( Subtotal = $428,112 )
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	18	6/15/2020	NON-COMPETING CONTINUATION	$428,112
														Subtotal = $428,112

Issue Date FY: 2019 ( Subtotal = $423,495 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	17	8/28/2019	COMPETING CONTINUATION	$423,495
2019	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	16	7/12/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $423,495

Issue Date FY: 2018 ( Subtotal = $315,057 )
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	16	5/5/2018	NON-COMPETING CONTINUATION	$315,057
														Subtotal = $315,057

Issue Date FY: 2017 ( Subtotal = $315,260 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	15	4/21/2017	NON-COMPETING CONTINUATION	$283,734
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	15	6/14/2017	NON-COMPETING CONTINUATION	$31,526
														Subtotal = $315,260

Issue Date FY: 2016 ( Subtotal = $312,285 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	14	4/29/2016	NON-COMPETING CONTINUATION	$312,285
														Subtotal = $312,285

Issue Date FY: 2015 ( Subtotal = $307,708 )
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	13	5/13/2015	NON-COMPETING CONTINUATION	$307,708
														Subtotal = $307,708

Issue Date FY: 2014 ( Subtotal = $315,741 )
2014	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	12	8/15/2014	COMPETING CONTINUATION	$315,741
2014	2013	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	11	8/15/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $315,741

Issue Date FY: 2013 ( Subtotal = $288,211 )
2013	2013	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	11	5/21/2013	NON-COMPETING CONTINUATION	$14,881
2013	2013	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	11	4/4/2013	NON-COMPETING CONTINUATION	$273,330
														Subtotal = $288,211

Issue Date FY: 2012 ( Subtotal = $391,961 )
2012	2012	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	002	10	8/9/2012	NON-COMPETING CONTINUATION	$0
2012	2012	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	9	2/1/2012	SUPPLEMENT FOR EXPANSION	$24,369
2012	2012	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	10	3/20/2012	NON-COMPETING CONTINUATION	$367,592
														Subtotal = $391,961

Issue Date FY: 2011 ( Subtotal = $303,700 )
2011	2011	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	001	9	6/20/2011	NON-COMPETING CONTINUATION	$18,980
2011	2011	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	9	3/11/2011	NON-COMPETING CONTINUATION	$284,720
														Subtotal = $303,700

Issue Date FY: 2010 ( Subtotal = $316,355 )
2010	2010	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	8	3/8/2010	NON-COMPETING CONTINUATION	$316,355
														Subtotal = $316,355

Issue Date FY: 2009 ( Subtotal = $319,550 )
2009	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	7	9/21/2009	COMPETING CONTINUATION	$319,550
														Subtotal = $319,550

Issue Date FY: 2007 ( Subtotal = $266,250 )
2007	2007	CORNELL UNIVERSITY, ENDOWED COLLEGES	EAST HILL PLAZA	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	6	4/6/2007	NON-COMPETING CONTINUATION	$266,250
														Subtotal = $266,250

Issue Date FY: 2006 ( Subtotal = $274,201 )
2006	2006	CORNELL UNIVERSITY, ENDOWED COLLEGES	EAST HILL PLAZA	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	5	3/15/2006	NON-COMPETING CONTINUATION	$274,201
														Subtotal = $274,201

Issue Date FY: 2005 ( Subtotal = $281,700 )
2005	2005	CORNELL UNIVERSITY, ENDOWED COLLEGES	EAST HILL PLAZA	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	4	6/9/2005	NON-COMPETING CONTINUATION	$281,700
														Subtotal = $281,700

Issue Date FY: 2004 ( Subtotal = $300,600 )
2004	2004	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	500 WEST 185TH STREET	NEW YORK-NEW YORK	NY	10033		USA	Child Health and Human Development Extramural Research	000	2	2/24/2004	NON-COMPETING CONTINUATION	$300,600
														Subtotal = $300,600

Issue Date FY: 2003 ( Subtotal = $300,600 )
2003	2003	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	500 WEST 185TH STREET	NEW YORK-NEW YORK	NY	10033		USA	Population Research	000	1		NEW	$300,600
														Subtotal = $300,600

Grand Total All Awards = $7,352,432

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Regulation of MutL-gamma function in mediating crossing over in mammalian meiosis

Award Number: R01HD041012

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2003

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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