An Undiscovered Class of Cancer Genes ABSTRACT The central hypothesis of this project is that there exists a large, highly-conserved class of genes/proteins that regulate levels of spontaneous DNA damage in all living cells, and so are the proximal, upstream effectors/modulators of genome instability. These are proposed to include many highly conserved essential genes that, in humans, are expected to constitute a "new" class of cancer genes distinct from (upstream of) the two main recognized classes: genomic-caretaker and gatekeeper genes. However these "damage-control" genes/proteins have remained undiscovered and unrecognized because of two limitations. First, no technology existed to assay spontaneous/endogenous DNA damage, particularly DNA breakage, directly in living cells. Thus, factors that affect the levels of endogenous DNA damage have mostly not been assayed, and not considered. Second, many of the damage-control genes are likely to be essential for organism viability, and current forward-genetic approaches in model organisms, which might otherwise have found some of these genes, are biased against essential genes. We expect the damage-control genes to encompass at least the following: (1) normal metabolic pathways (carbon metabolism, etc.) that unavoidably produce toxic by-products that react with DNA causing base/nucleotide damage;(2) proteins/molecules that scavenge these by-products;(3) DNA replication components. (DNA breaks often result from replication into damage.) All of these are expected to be very highly conserved because they are so basic to life, and most are expected to be essential genes. The goals of this project are--(1) to develop a new methodological paradigm of forward genomics that will allow rapid identification of genes, including essential genes, of interest to any problem in biology;(2) using this paradigm, to find the damage-control genes in the simple model organism E. coli, identify their counterparts in human, then id

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
3DP1OD006429-03S1
Application #
8322231
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Wehrle, Janna P
Project Start
2009-09-30
Project End
2012-07-31
Budget Start
2011-10-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$37,391
Indirect Cost
$13,499
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030