Understanding the Mechanisms of DNA Mismatch Repair

Steven Pike

Photo of an experiment where we were testing the ability of different strains of yeast to perform DNA repair .

Photo of an experiment where we were testing the ability of different strains of yeast to perform DNA repair

Undergraduate Student Project

Introduction

Hello my name is Steven Pike and I am currently a senior chemical engineering student at UB. For the past two years I have been working with Dr. Jennifer Surtees in her lab that studies genomic stability.

Genomic stability refers to the idea that our DNA is perfectly replicated each time our cell divides. Genomic instability is when you have errors in DNA replication and the new strand is mutated.  If our cells lack genomic stability, then this increases the chances of a cancer causing mutation to occur. Understanding how our cells have adapted to correctly replicate DNA is the core of what we study.

One of the ways evolution has allowed our cells to prevent these errors from occurring is through DNA repair pathways. These are biological pathways designed to recognize and correct these errors. One of these specific pathways is the mismatch repair (MMR) pathway, which corrects insertions, deletions or mis-incorporation of correct nucleotide (building blocks of DNA) into the new strand. One of the proteins involved in this pathway is Msh2-Msh3. It is responsible for recognizing this type of error, and it recruits other proteins to help fix the problem. My lab is interested in understanding the mechanism for how Msh2-Msh3 interacts with DNA in different contexts. Specifically, we want to understand whether or not the interactions between Msh2-Msh3 and the DNA are what decides whether or not Msh2-Msh3 will initiate MMR, or other DNA repair pathways.

Abstract

The mismatch repair (MMR) system functions to correct errors in DNA replication. Defects in MMR result in increased rates of mutations leading to genome instability. The first step in MMR is the recognition of an error by a MutS homolog (MSH) protein complex.  Msh2-Msh3 specifically recognizes slippage events that result in extra-helical nucleotides.  Msh2-Msh3 also directs a specialized form of double strand DNA break repair (DSBR) and promotes trinucleotide repeat (TNR) expansions.  The interactions between Msh2-Msh3 and the DNA substrate backbone are not well understood. To understand how Msh2-Msh3 interacts with different DNA substrates and initiate different DNA metabolic pathways, we created point mutations in S. cerevisiae MSH3 and measured mutation rates. Our preliminary data indicate small increases in mutation rate. Future work will assess the activity of msh3 alleles in MMR,  DSBR and TNR expansions.

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