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Mechanism of action of the bacterial addiction module Phd-Doc

by
Mohan Liu
B.Sc., 2000
Nankai University
China

Graduate Program in Molecular Genetics, Microbiology and Immunology

Thesis Advisor: Nancy Woychik, PhD

Wednesday, April 22, 2009
2:00 pm


Abstract

We investigated the mode of action of the Doc toxin of the Phd-Doc addiction module harbored by bacteriophage P1 in both bacteria and yeast. Doc expression resulted in rapid cell growth arrest and marked inhibition of translation. However, Doc did not cleave mRNA as do several other addiction module toxins whose activities result in translation inhibition; instead, Doc significantly stabilized mRNA. Doc stabilized polysomes and associated with the 30S subunit, similar to hygromycin B (HygB) treatment. HygB also competed with ribosome-bound Doc, while HygB-resistant mutants suppressed Doc toxicity. Surprisingly, Doc toxicity was associated with the cleavage of 16S rRNA near the HygB binding site at position 1403 in helix 44 comprising the A, P and E sites in 70S and 30S ribosomal, but not polysome, fractions. In yeast, Doc also inhibited translation and associated with the small ribosomal subunit. Thus, in prokaryotes, Doc appears to inhibit elongation by both binding to actively translating ribosomes and directly or indirectly mediating site-specific cleavage of 16S rRNA in 70S ribosomes and 30S ribosomal subunits. Based on our preliminary evidence, we believe that Doc may behave similarly in eukaryotes.


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