Our hypothesis is that TREX1 and TREX2 are exonucleases with 3'-?5'excision activity that is important for removing problematic nucleotides during either DNA replication and/or DMArepair and our goal is to study these proteins in cells and mice. Currently TREX1 and TREX2 are thought to be exonucleases based on their homology to three exonuclease sequence motifs of E. coli DNA pol 1 large fragment and bacteriophage T4 DNA pol and based on their 3'-?5'exonuclease activity in vitro. However, at this time there is no more published information defining their cellular function. Thus, TREX1 and TREX2 are potentially important for maintaining genomic stability and perhaps cancer prevention. There are three aims that define TREX1 and TREX2.
Aim 1 : to elucidate fundamental TREX1 and TREX2 biochemical functions. There three known biochemical functions: 1) self association 2) exonuclease activity, 3) and DNA binding activity. We have setup in vitro assays to observe these activities and our goal is to generate impaired forms of TREX1 and TREX2 that perform some but not all of these activities.
Aim 2 : to discover the biological importance of TREX1 and TREX2 by analyzing genetically altered mouse embryonic stem (ES) cells. We will compare a mutation that is null to mutations that alter some but not all functions as discovered in aim 1. At this time we have generated TREX2-null ES cells and our preliminary results demonstrate that TREX2 is indeed involved in genome maintenance. We show TREX2-null cells exhibit altered sensitivity to some DNA damaging agents and TREX2-null cells exhibit genomic instability including gross chromosomal rearrangements.
Aim 3 : to analyze TREX-null mice in wild type and p53 mutant backgrounds. Wewill perform a life span analysis and determine the onset, incidence and spectra of age-related characteristics including cancer and genomic instability. The impact p53-mediated responses to damaged DNA will be determined by studying double-mutant mice. Completion of this proposal will greatly facilitate our understanding of TREX1 and TREX2 for maintaining genome stability and for preventingcancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123203-05
Application #
8015359
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Okano, Paul
Project Start
2007-04-01
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$269,078
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Kim, Tae Moon; Son, Mi Young; Dodds, Sherry et al. (2015) RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway. Nucleic Acids Res 43:893-903
Kim, Tae Moon; Son, Mi Young; Dodds, Sherry et al. (2014) Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks. Mutat Res 766-767:66-72
Kim, Tae Moon; Son, Mi Young; Dodds, Sherry et al. (2014) Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks. Mutat Res 766-767:66-72
Hasty, Paul; Livi, Carolina B; Dodds, Sherry G et al. (2014) eRapa restores a normal life span in a FAP mouse model. Cancer Prev Res (Phila) 7:169-78
Hu, Lingchuan; Kim, Tae Moon; Son, Mi Young et al. (2013) Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes. Nature 501:569-72
Kim, Tae Moon; Rebel, Vivienne I; Hasty, Paul (2013) Defining a genotoxic profile with mouse embryonic stem cells. Exp Biol Med (Maywood) 238:285-93
Kim, Tae Moon; Ko, Jun Ho; Hu, Lingchuan et al. (2012) RAD51 mutants cause replication defects and chromosomal instability. Mol Cell Biol 32:3663-80
Choi, Yong Jun; Son, Mi Young; Hasty, Paul (2011) One-step knockin for inducible expression in mouse embryonic stem cells. Genesis 49:92-7
Dumitrache, Lavinia C; Hu, Lingchuan; Son, Mi Young et al. (2011) Trex2 enables spontaneous sister chromatid exchanges without facilitating DNA double-strand break repair. Genetics 188:787-97
Kim, Tae Moon; Ko, Jun Ho; Choi, Yong Jun et al. (2011) The phenotype of FancB-mutant mouse embryonic stem cells. Mutat Res 712:20-7

Showing the most recent 10 out of 13 publications