DNA replication is a fundamental process on which all organisms depend for faithful passage of genetic material from one generation to the next. The DNA replication process is often "stressed" either by mutations or by exogenous reagents that can cause DNA damage or impediments to the replication machinery. Replication stress can give rise to genomic instability and may ultimately lead to diseases including cancer. My main research interest is how defective replication cause genomic instability. The general hypothesis governing this proposal is that single-stranded DNA (ssDNA) production upon replication fork stalling and destablization in replication checkpoint-deficient mutants is a potentially lethal event that prevents complete synthesis of the genome, causes chromosomal breakage, and ultimately genomic instability.
The specific aims of this project are: 1. Investigate the link between extensive ssDNA formation during replication stress and chromosome breakage using the genome-wide ssDNA and chromosome breakage mapping techniques developed by the applicant in combination with other genetic approaches. 2. Elucidate the mechanism/cause of replication fork instability in checkpoint mutants in HU by examining the structural/compositional changes that occur in the replication complex upon replication stress by a minichromosome purification system coupled with mass spectrometry. 3. Identify origins of replication and chromosome fragile sites in humans using a combination of ssDNA and chromosome breakage mapping that have been adapted for the mammalian systems.

Public Health Relevance

The proposed project will have a direct impact on our understanding of two important features of the human genome, origins of replication and chromosome fragile sites, and how defects in the replication process induce genomic instability and human diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Transition Award (R00)
Project #
5R00GM081378-04
Application #
8204426
Study Section
Special Emphasis Panel (NSS)
Program Officer
Reddy, Michael K
Project Start
2007-07-30
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$223,284
Indirect Cost
$73,954
Name
Upstate Medical University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210