Wednesday, January 15, 2025 1/15/2025

Enzymology of Mismatch Repair in Yeast

Award Number: R01GM050006
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY DNA mismatch repair (MMR) plays critical roles in eukaryotic cells including: 1) suppressing mutations that result from misincorportation errors during DNA replication that escape DNA polymerase proofreading; 2) suppressing mutations that result from misincorporation events that occur due to chemical modification of DNA or DNA precursors; 3) preventing genome rearrangements due to recombination between divergent DNA sequences; 4) correcting mispaired bases in recombination intermediates; and 5) detecting DNA damage and activating signaling pathways linked to cellular responses, including cell cycle control and cell death. Consequently, MMR defects cause increased rates of accumulating mutations and genome rearrangements resulting in a characteristic genome instability signature and resistance to killing by some DNA damaging agents. In humans, MMR defects underlie both inherited and sporadic cancers, cause tumors to become resistant to some chemotherapy agents and appear to cause quite striking sensitivity of cancers to immunotherapy. Thus, a better understanding of MMR pathways and the consequences of MMR defects will impact human health by: 1) informing our understanding of MMR status; and 2) guiding improvements in the development and use of therapies for MMR-deficient cancers. The proposed studies use Saccharomyces cerevisiae as a model system to study the mechanisms of the conserved eukaryotic MMR pathways. The following lines of investigation will be carried out: 1) genetic approaches will be used to study Msh2- and Mlh1-interacting proteins, identify new MMR proteins and study the activation of the Mlh1-Pms1 endonuclease; 2) reconstitution approaches will be used to study the MMR pathways in which mispair excision is mediated by either Exo1 or the Rad27 endonuclease focusing on mispair excision mechanisms, the recruitment of Exo1 and Rad27 to MMR reactions and whether DNA pol ε can act in Rad27-mediated MMR; 3) reconstitution approaches will be used to study MMR pathways that are dependent on the Mlh1-Pms1 endonuclease including pathways where Mlh1-Pms1 initiates mispair excision by Exo1 and Rad27 and a novel, newly reconstituted pathway where mispair excision is mediated only by Mlh1-Pms1; and, 4) individual steps in MMR reactions will be studied primarily by investigating the protein-protein interactions and higher order complexes of proteins that drive MMR using Surface Plasmon Resonance and single molecule biochemistry methods. The long-term goal of these studies is to develop a detailed understanding of the biochemical and molecular mechanisms of MMR and how cells utilize MMR to prevent mutations and genome rearrangements. Because MMR is highly conserved, the results from studies of S. cerevisiae MMR will provide insights into the mechanisms of MMR in human cells. Consequently, this project will provide insights that can be applied to understanding the genetics of human cancers and the biology of MMR defects in human cancers in addition to providing a basic understanding of MMR mechanisms.


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: 2024 ( Subtotal = $406,850 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	36	6/7/2024	NON-COMPETING CONTINUATION	$406,850
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	35	11/7/2023	COMPETING CONTINUATION	$138,443
2024	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	34	11/7/2023	NON-COMPETING CONTINUATION	-$138,443
														Subtotal = $406,850

Issue Date FY: 2023 ( Subtotal = $406,850 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	35	6/8/2023	COMPETING CONTINUATION	$406,850
2023	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	34	5/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $406,850

Issue Date FY: 2022 ( Subtotal = $400,000 )
2022	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	34	11/10/2021	NON-COMPETING CONTINUATION	$360,000
2022	2022	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	34	6/9/2022	NON-COMPETING CONTINUATION	$40,000
														Subtotal = $400,000

Issue Date FY: 2021 ( Subtotal = $400,000 )
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	33	11/24/2020	NON-COMPETING CONTINUATION	$360,000
2021	2021	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	33	2/22/2021	NON-COMPETING CONTINUATION	$40,000
														Subtotal = $400,000

Issue Date FY: 2020 ( Subtotal = $468,861 )
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	32	2/27/2020	NON-COMPETING CONTINUATION	$40,001
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	32	8/8/2020	SUPPLEMENT FOR EXPANSION	$68,860
2020	2020	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	32	11/22/2019	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $468,861

Issue Date FY: 2019 ( Subtotal = $400,000 )
2019	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	31	5/13/2019	COMPETING CONTINUATION	$61,779
2019	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	31	1/29/2019	COMPETING CONTINUATION	$400,000
2019	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	30	5/13/2019	NON-COMPETING CONTINUATION	-$61,779
														Subtotal = $400,000

Issue Date FY: 2018 ( Subtotal = $381,090 )
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	30	11/21/2017	NON-COMPETING CONTINUATION	$342,980
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	30	5/24/2018	NON-COMPETING CONTINUATION	$38,110
														Subtotal = $381,090

Issue Date FY: 2017 ( Subtotal = $381,090 )
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	29	8/2/2017	NON-COMPETING CONTINUATION	$38,109
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	29	11/16/2016	NON-COMPETING CONTINUATION	$342,981
														Subtotal = $381,090

Issue Date FY: 2016 ( Subtotal = $381,090 )
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	28	11/20/2015	NON-COMPETING CONTINUATION	$342,981
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	28	3/1/2016	NON-COMPETING CONTINUATION	$38,109
														Subtotal = $381,090

Issue Date FY: 2015 ( Subtotal = $391,150 )
2015	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	27	1/19/2015	COMPETING CONTINUATION	$391,150
														Subtotal = $391,150

Issue Date FY: 2014 ( Subtotal = $405,935 )
2014	2014	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	26	11/18/2013	NON-COMPETING CONTINUATION	$365,341
2014	2014	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	26	4/2/2014	NON-COMPETING CONTINUATION	$40,594
														Subtotal = $405,935

Issue Date FY: 2013 ( Subtotal = $391,726 )
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	25	11/19/2012	NON-COMPETING CONTINUATION	$365,340
2013	2013	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	25	6/24/2013	NON-COMPETING CONTINUATION	$26,386
														Subtotal = $391,726

Issue Date FY: 2012 ( Subtotal = $405,932 )
2012	2012	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	24	3/12/2012	NON-COMPETING CONTINUATION	$33,346
2012	2012	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	24	12/5/2011	NON-COMPETING CONTINUATION	$372,586
														Subtotal = $405,932

Issue Date FY: 2011 ( Subtotal = $405,928 )
2011	2011	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	23	11/26/2010	COMPETING CONTINUATION	$405,928
														Subtotal = $405,928

Issue Date FY: 2010 ( Subtotal = $399,496 )
2010	2010	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	22	3/10/2010	NON-COMPETING CONTINUATION	$36,318
2010	2010	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	22	11/23/2009	NON-COMPETING CONTINUATION	$363,178
														Subtotal = $399,496

Issue Date FY: 2009 ( Subtotal = $445,338 )
2009	2009	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	21	3/25/2009	NON-COMPETING CONTINUATION	$39,187
2009	2009	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	21	11/11/2008	NON-COMPETING CONTINUATION	$352,680
2009	2009	LUDWIG INSTITUTE FOR CANCER RESEARCH	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	002	21	7/16/2009	SUPPLEMENT FOR EXPANSION	$53,471
														Subtotal = $445,338

Grand Total All Awards = $9,903,118

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Enzymology of Mismatch Repair in Yeast

Award Number: R01GM050006

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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