PO1: Structure and Function of DNA Repair Enzymes and Cancer

MMG is pleased to host Dr. Sylvie Doublié's  PO1 Program Project Grant. According to the National Institutes for Health, a Program Project Grant (PO1) is "an assistance award for the support of a broadly based multidisciplinary research program that has a well-defined central research focus or objective. Interrelationships between component projects are expected to result in a greater contribution to the program goals than if each project were pursued separately. It may also include support for commonly shared resources (cores) required to carry out the component research projects. Research cores enable projects to expedite scientific discovery and allow personnel to focus on their own experiments. This grant will have a major positive impact on cancer therapies and improve public health outcomes.

Dr. Doublié's PO1, Structure and Function of DNA Repair Enzymes and Cancer (UVM 5P01CA098993-12), was awarded in 2018. 

Doublie Lab

Public Health Relevance Statement: Cells have the remarkable capability to repair DNA damage by several pathways, including base excision repair (BER). Failure to repair DNA damage has the potential to lead to cancer. We have and will continue to identify functional human germline mutations that are likely to confer cancer susceptibility to individuals carrying them, as well as mutations in tumors that convey sensitivity or resistance to particular cancer treatments. Importantly, using a combination of functional approaches, we will gain insight as to why the proteins produced by these mutant genes may influence carcinogenesis or cancer treatment. As personalized medicine becomes the paradigm, these studies will have a major impact on cancer etiology and prevention as well as provide the basis for predictive biomarkers for cancer therapies.

The PO1 has four projects and three cores, which are summarized below.


Project One:

Single Nucleotide Polymorphisms in DNA Repair Genes and Cancer

Public Health Relevance Statement: The relevance of these studies is that they have the potential to elucidate molecular mechanisms associated with the development of cancer and with its therapy. The results are likely to be informative in clinical decision- making processes.

Project Two:

Structure/function studies of the oxidative DNA glycosylases

Public Health Relevance Statement: These biochemical and structural biology studies will advance our understanding of how DNA repair enzymes recognize and repair DNA lesions and how mutations in these enzymes contribute to individual cancer risk. Understanding how mutations in DNA glycosylases affect their function will inform prognosis and cancer treatment.


Project Three:

Repair in Nucleosomes

Public Health Relevance Statement: Defects in the enzymes that repair oxidatively damaged DNA can increase the risk of cancer. Project 3 will investigate molecular mechanisms that regulate these enzymes and enable them to function properly in cells. These studies will provide further insight into cancer risks linked to oxidative damage in DNA.

Project Four:

Single-Molecule Analysis of Interactions Between Base Excision Repair Enzymes and their Targets

Public Health Relevance Statement: Aberrant DNA repair is a key cause of genomic instability leading to cancer and tumor progression. The results of the studies proposed in Project 4 will provide mechanistic insights into how mutations in DNA repair genes in the normal population and in tumors contribute to altered DNA repair capacity and enhance our understanding of carcinogenesis. Information from these studies should also lead to novel therapeutic strategies for tumors containing mutations in DNA repair genes.



Core A: Bioinformatics Core

Public Health Relevance Statement: Experiments proposed by the Program Project characterize the consequences of natural human genetic variation in Base Excision Repair enzymes for carcinogenesis and cancer therapy. Core A provides informatics and statistics services that support design and analysis of these experiments

Core Director:

Julie Dragon, Ph.D.

Core B: Protein Expression and Cell Culture Core

Public Health Relevance Statement: Core B will play an integral role in providing purified proteins and mammalian cell culture lines to all Projects. We expect the results of the studies proposed within this Program Project to advance our understanding of how DNA repair protein variants contribute to cancer susceptibility.

Core Director:

Sylvie Doublié, Ph.D.

Core C: Administrative Core

Public Health Relevance Statement: Core C provides administrative support to all of the projects and other cores in this program that studies how mutations in DNA repair genes in the normal population and in tumors contribute to altered DNA repair capacity. This Program Project will both contribute to our understanding of basic cancer biology and provide the basis for new approaches to cancer therapy.

Core Director:

Sylvie Doublié, Ph.D.