Homologous recombination that takes place in prophase of meiosis I is required for reproduction in humans and other eukaryotes. Defects in meiotic homologous recombination in humans cause infertility, miscarriages, and Down and Turner syndromes. The human MLH1-MLH3 complex (MutL?) has been implicated in meiotic homologous recombination, but its function in this process has not been defined. In addition to having a key function in meiotic homologous recombination human MutL? has other functions that are poorly understood. One of these functions is required for triplet repeat DNA expansion, a process that causes several neurodegenerative diseases. A lack of information about the action of MutL? in meiotic recombination and triplet repeat DNA expansion is a major gap in our understanding of these key biological processes. Our preliminary data support the hypothesis that human MutL? functions as an ATP-dependent endonuclease in meiotic recombination and triplet repeat DNA expansion. The goal of this project is to investigate MutL? and its potential interactors and establish functional assays for future studies of MutL? and MutL?-dependent mechanisms.
In Aim 1, we will study endonuclease and ATPase activities of MutL? in assays that will produce novel insights into the functions of MutL? in meiotic homologous recombination and triplet repeat instability.
In Aim 2, we will identify proteins that interact with human MutL?. The results of the proposed research will advance our understanding of MutL? and will permit new studies into the mechanisms of MutL?-dependent meiotic recombination and triplet repeat DNA expansion.

Public Health Relevance

Defects in meiotic homologous recombination cause infertility, miscarriages, and Down and Turner syndromes, and triplet repeat DNA expansions trigger ~30 neurodegenerative diseases. The human MLH1-MLH3 complex has been implicated in both meiotic homologous recombination and expansions of certain triplet repeat DNAs, but its action in these processes is unknown. This project will provide novel insights into the action of human MLH1-MLH3 complex and the results will permit new studies into the mechanisms of meiotic recombination and triplet repeat expansions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD098293-01A1
Application #
9893399
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Taymans, Susan
Project Start
2020-01-01
Project End
2021-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Southern Illinois University Carbondale
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939007555
City
Carbondale
State
IL
Country
United States
Zip Code
62901