Kuo et al 2009 abstract

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Kuo et al 2009 abstract Powered By Docstoc
					 The tmRNA system is essential when transcription is blocked

                         by DNA-protein crosslinks

  H. Kenny Kuo1, Ashok S. Bhagwat2 and Kenneth N. Kreuzer1,*


       Anticancer drug 5-azacytidine (aza-C) induces crosslinks between cytosine

methyltransferase and DNA as the drug inhibits the methylation reaction. We found that

mutants defective in the tmRNA translational quality control system are hypersensitive to

aza-C. Hypersensitivity of these mutants requires expression of active methyltransferase,

indicating that hypersensitivity is dependent on DNA-methyltransferase crosslink

formation. Furthermore, the tmRNA pathway is activated upon aza-C treatment in cells

expressing methyltransferase, resulting in increased SsrA tagging of cellular proteins.

These results support a “chain-reaction” model, in which transcription complexes

blocked by aza-C-induced DNA-protein crosslinks result in ribosomes stalling on the

attached nascent transcripts, and the tmRNA pathway is invoked for cleaning up the

resulting pile-ups. In support of this model, an ssrA mutant is also hypersensitive to

antibiotic streptolydigin, which blocks RNA polymerase elongation. These results reveal

a novel role for the tmRNA system in clearance of coupled transcription/translation

complexes in which RNA polymerase has become blocked.