Homopolymeric Tracts: Potential Non-mutator/mutator Switches

Open Access
Author:
Chung, Steve
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Sarah Ellen Ades, Honors Advisor
  • James Endres Howell, Faculty Reader
  • Scott Brian Selleck, Faculty Reader
  • Sarah Ellen Ades, Thesis Supervisor
Keywords:
  • Homopolymeric Tract
  • antibiotic resistance
  • MRSA
Abstract:
MRSA is defined as a strain of Staphylococcus aureus that has the gene mecA. While β-lactam antibiotic resistance has been linked to mecA, it does not fully explain the rapid acquisition of antibiotic resistance. A past clinical study identified a MRSA strain that acquired resistance to the last line of defense drug. After treatment with vancomycin, the infection still did not clear. MRSA isolates from the study were sequenced, and it was found that the MRSA strains were acquiring mutations quickly. Among the genes found to be mutated, the mutL gene was of interest because of a homopolymeric tract located midway in the gene. Homopolymeric tracts are prone to slippage, making expansion and contraction highly likely. This means that mutL could be frameshifted at a high probability, causing a nonfunctional truncated mutL protein. The knockout of the mutL gene leads to a mutator phenotype, since the gene is responsible for DNA mismatch repair. In this study, we showed that a frameshift, contraction of the homopolymeric tract, in mutL leads to an increase of mutation rate in MRSA, which might have indirectly supported the bacteria in developing antibiotic resistance at a rate 10-times faster than the wild-type MRSA strain. In addition, the study extends the concept of a homopolymeric tract as a potential gene regulator in the ClpX gene. Preliminary data suggests that long homonucleotide tracts located in other genes may play a role in β-lactam antibiotic resistance.