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Mechanisms of Myotonic Dystrophy Type 2-causing CCTG DNA Repeat Instability

Award Number: SC3GM127198
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: 04/13/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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Mechanisms of Myotonic Dystrophy Type 2-causing CCTG DNA Repeat Instability - Project Summary Expansions of simple DNA repeats cause over 30 heritable neuromuscular and neurodegenerative disorders. For example, the two major types of myotonic dystrophy are repeat expansion disorders. DM1 is caused by long CTG trinucleotide repeats in the 5’ UTR of DMPK whereas DM2 is caused by long tetranucleotide CCTG repeats in an intron of ZNF9. Experimental systems from bacteria to Drosophila to human cells have been established to investigate the mechanisms by which CTG sequences expand, or increase in length. Such studies have implicated specific roles of DNA replication, DNA repair, and transcription in the expansion process. In contrast, CCTG repeats are more poorly understood, and it is unclear whether the same molecular mechanisms contributing to CTG repeat expansions also apply to CCTG repeats. This is a pressing question since individuals with DM2 have, on average, 5000 CCTG repeats in ZNF9. Moreover, the incidence of such long repeat lengths make delineating the mechanism of repeat contraction particularly attractive as a therapeutic prospect. Thus, the work proposed here seeks to establish budding yeast Saccharomyces cerevisiae as a robust experimental system to investigate CCTG repeat expansions and contractions. Specifically, the proposed research will investigate the genetic control of CCTG repeat instability and define the proteins and chromatin modifications associated with CCTG repeats. My overarching hypothesis is that the genes involved in CCTG repeat instability may partially overlap with those of CTG repeats, but there will be a unique set of players owing to the distinct effect of CCTG repeats on DNA secondary structure, chromatin state, and replication dynamics. Towards this end, I will determine the effect of CCTG repeat length, orientation, and transcription on expansions and contractions. I will identify genetic and molecular determinants of CCTG repeat instability using both candidate and unbiased genetic screening approaches. In particular, identifying genes involved in CCTG repeat contraction through an unbiased genetic screen will potentially uncover genes that have no previously known role in DNA repeat maintenance. Finally, I will define the protein and chromatin landscape at CCTG repeats and compare it to CTG repeats using the innovative CRISPR-based Chromatin Affinity Purification with Mass Spectrometry (CRISPR-ChAP-MS) approach. Overall, the proposed research will have a major impact on our understanding of the molecular biology of CCTG repeats, which has significant implications for human health and disease. This work will identify potential targets for preventative and therapeutic interventions for DM2 and also serve as a model for understanding the replication and maintenance of microsatellite repeats responsible for other repeat expansion disorders.


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 = -$9,654 )
2024	2021	CALIFORNIA STATE UNIVERSITY SAN MARCOS CORP	333 S TWIN OAKS VALLEY RD	SAN MARCOS	CA	92096	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	12/5/2023	NON-COMPETING CONTINUATION	-$9,654
														Subtotal = -$9,654

Issue Date FY: 2021 ( Subtotal = $111,750 )
2021	2021	CALIFORNIA STATE UNIVERSITY SAN MARCOS CORPORATION	333 S TWIN OAKS VALLEY RD	SAN MARCOS	CA	92096	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	3/23/2021	NON-COMPETING CONTINUATION	$111,750
														Subtotal = $111,750

Issue Date FY: 2020 ( Subtotal = $97,050 )
2020	2020	CALIFORNIA STATE UNIVERSITY SAN MARCOS CORPORATION	333 S TWIN OAKS VALLEY RD	SAN MARCOS	CA	92096	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	3/26/2020	NON-COMPETING CONTINUATION	$97,050
														Subtotal = $97,050

Issue Date FY: 2019 ( Subtotal = $111,750 )
2019	2019	CALIFORNIA STATE UNIVERSITY SAN MARCOS CORPORATION	333 S TWIN OAKS VALLEY RD	SAN MARCOS	CA	92096	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/11/2019	NON-COMPETING CONTINUATION	$111,750
														Subtotal = $111,750

Issue Date FY: 2018 ( Subtotal = $99,500 )
2018	2018	CALIFORNIA STATE UNIVERSITY SAN MARCOS CORPORATION	435 E CARMEL ST	SAN MARCOS	CA	92078	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	4/13/2018	NEW	$99,500
														Subtotal = $99,500

Grand Total All Awards = $410,396

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Mechanisms of Myotonic Dystrophy Type 2-causing CCTG DNA Repeat Instability

Award Number: SC3GM127198

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: 04/13/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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