Genomic Instability at DNA Nicks Our goal is to understand the mechanisms by which DNA nicks can initiate events that lead to genomic instability. Nicks are the most common form of DNA damage. Human cells experience tens of thousands of nicks each day, from reactive oxygen species, ionizing radiation, and as intermediates in many pathways of DNA repair. Nicks can be efficiently and faithfully repaired by the single strand break repair pathway, and they have not been viewed as a threat to genomic stability. Recent results from our laboratory challenge that view. We have shown that nicks can initiate homology-directed repair (HDR), a source of two forms of genomic instability common in tumors, copy number alteration (CNA) and loss of heterozygosity (LOH). HDR at nicks is distinct from HDR at double strand breaks. It is associated with transcription and preferentially repairs the transcribed DNA strand. HDR at nicks can proceed via a very efficient alternative pathway that is normally suppressed by canonical HDR, suggesting that alternative HDR is active in tumors that are deficient in canonical HDR. We propose to define the mechanisms by which nicks initiate HDR and genomic instability, by carrying out the following three specific Aims:
Aim 1. To define the factors and pathways that carry out and regulate nick-initiated HDR.
Aim 2. To establish whether the cell cycle regulates alternative HDR at nicks.
Aim 3. To determine how HDR at nicks is coupled to transcription. The proposed research will enable us to identify tumors at risk for nick-initiated HDR, and minimize their exposure to nicks. It will identify targets for therapies that diminish nick-initiated genomic instability, as well as targets for therapies that activate genomic instability to create DNA damage that kills cells.

Public Health Relevance

Nicks are the most common form of DNA damage, and while they can be efficiently repaired, they can also lead to genomic instability. The goal of the proposed research is to define the mechanisms that promote and prevent genomic instability at nicks. This will enable us to identify tumors at risk for nick-initiated HDR and to develop therapies that diminish nick-initiated genomic instability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA183967-01A1
Application #
8815606
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2014-09-09
Project End
2019-08-31
Budget Start
2014-09-09
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$313,541
Indirect Cost
$106,041
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195