Mouse Model for Chemical and Radiation Mutagenesis

Project Details

Description

DESCRIPTION (provided by applicant): There are distinct kinds of DNA damage
caused by environmental chemicals and ionizing radiation (IR). However, double
strand breaks (DSBs) in DNA are among the most serious. Failure to repair or
gross misrepair of DSBs results in cell death or sometimes, in the case of
humans, somatic cell diseases such as cancer. Knockout mice and work with
cultured cells has demonstrated that DSB repair in vertebrates is much more
complex than previously imagined. It was thought that most DSB repair in
mammals was by non-homologous end-joining (NHEJ), but it is now clear that
homologous recombination (HR) and other homology-directed processes play key
roles in maintaining genome integrity. Further, these mechanistically distinct
processes interact in novel ways with each other as well as those for mismatch
repair (MMR) and apoptosis. We developed a mouse model that detects somatic
genetic endpoints of DSB and other kinds of repair. These include mitotic
recombination (MR), interstitial deletion and chromosomal deletion and
translocation, all of which may result in loss of heterozygosity (LOH). This
model also allows for the quantitation and characterization of point mutation,
chromosome loss and epigenetic gene inactivation leading to LOH - key
biological events to the etiology of cancer and diseases such as polycystic
kidney disease. By introducing knockout defects of DNA repair or apoptosis into
our model and by exposing these mice to IR or DNA cross-linking agents such as
mitomycin C and cisplatin we will begin to understand the roles and regulation
of competing DSB repair processes. Specific aims include: 1. To characterize
the LOH frequency and spectrum of DAP-resistant (DAPR) skin fibroblasts and T
cells in Aprtneo/+ mice after in utero or adult exposure to ionizing radiation
(IR). 2. To investigate the effect of mitomycin C on LOH in Aprtneo/+ mice. 3.
To introduce deficiency for each of the MMR gene products and note effects on
the MR stringency requirement for DNA sequence homology. 4. To investigate
whether DSB and MMR repair pathways both participate in repair of damage
induced by mitomycin C or cisplatin. 5. To introduce Ku70 deficiency to test
whether or not NHEJ and HR have overlapping functions. 6. To introduce DNA-PKcs
deficiency to test whether or not Ku and DNA-PKcs participate in distinct as
well as common DSB repair pathways.
StatusFinished
Effective start/end date9/15/027/31/08

Funding

  • National Institutes of Health: $379,614.00
  • National Institutes of Health: $388,750.00
  • National Institutes of Health: $388,750.00
  • National Institutes of Health: $388,750.00
  • National Institutes of Health: $388,750.00

ASJC

  • Environmental Science(all)
  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.