Impact of gastric cancer-associated mutations on the repair of oxidative DNA damage
Name:
Dr. Melike Caglayan
Email
caglayanm@ufl.edu
Phone
(352) 294-8383
Faculty Department/Division
Biochemistry and Molecular Biology
This project is primarily:
Basic
Research Project Description:
Base excision repair (BER), a vital guardian of genome, is a critical process for repairing DNA base lesions and abasic sites, thereby preventing the mutagenic and lethal consequences of DNA damage1-5. It is estimated that BER resolves over 50,000 DNA lesions per cell per day generated by endogenous reactive oxygen species and environmental toxicants6-12. BER pathway involves a series of sequential enzymatic steps, via a process known as “passing-the-baton” and requires the tightly coordinated function of the core proteins including downstream enzymes DNA polymerase (pol) β, DNA ligase I and IIIα13-16. BER pathway coordination is also facilitated by scaffolding proteins such as X-Ray Repair Cross Complementing 1 (XRCC1)17,18. How the multi-protein BER complex ensures accurate repair pathway coordination remains unclear.
DNA repair is mostly believed to be accurate and beneficial, but our biochemical studies have revealed that, in certain situations, BER responses can lead to mutagenic outcomes19-36. Indeed, our group has spearheaded to the effort to define the molecular determinants that dictate accurate BER30-36. Additionally, it is often thought that cancer-associated missense mutations will lead to reduced repair capacity37-58. Our investigations uniquely examine the idea that BER variants, both strategically designed and cancer-associated, adversely affect the repair pathway coordination and thereby accuracy. These studies will have important ramifications on current designs to develop DNA repair capacity assays as strategy to assess disease susceptibility or therapeutic efficacy, as it’s reasonable to predict that certain substitutions will not affect repair efficiency/capacity but will impact repair fidelity59-65. Thus, defining the molecular determinants that dictate BER accuracy, particularly in the context of pathway coordination, is critical to fully understand disease mechanisms and risk potential.
Does this project have an international component or travel?
No
Characterization of brain metabolism via magnetic resonance
Name:
Prof. Joanna Long
Email
jrlong@ufl.edu
Phone
(352) 294-8399
Faculty Department/Division
Biochemistry and Molecular Biology
This project is primarily:
Basic
Research Project Description:
This project is focused on developing new magnetic resonance modalities to measure brain metabolite levels in vivo. The current focus is on using preclinical high field 7 T – 18 T) MRI systems to demonstrate their utility in rodent models of healthy and aberrant metabolism. No prior experience with MRI/MRS is needed as you will be working directly with a staff scientist.
Does this project have an international component or travel?
No
Elucidating mechanism of oxidative DNA damage repair by cancer mutants
Name:
Dr. Melike Caglayan
Email
caglayanm@ufl.edu
Phone
(352) 294-8383
Faculty Department/Division
Biochemistry and Molecular Biology
This project is primarily:
Basic Research
Project Description:
Base excision repair (BER), a vital guardian of genome, is a critical process for repairing DNA base lesions and abasic sites, thereby preventing the mutagenic and lethal consequences of DNA damage. It is estimated that BER resolves over 50,000 DNA lesions per cell per day generated by endogenous reactive oxygen species and environmental toxicants. BER involves gap filling by DNA polymerase beta enzyme (Polβ) which has been reported to be mutated in 30% of a variety of human tumors such as lung, gastric, colorectal, and prostate cancer. Several of the cancer-associated polβ variants possess aberrant activity or fidelity during BER, and expression of these variants in cells induces cellular transformation and genomic instability. The project contributes to a complete understanding of how cancer-associated polβ variants leads to aberrant BER to define how defects in the system contribute to disease risk.
Does this project have an international component or travel?
No