Evolution of
the NMD pathway.
Michael Culbertson,
Amanda Ford, Eric Neeno-eckwall, Robert Zinkel, Wei Zheng, Qiaoning Guan
Genetics and Molecular Biology, University of Wisconsin, 1525 Linden Dr.,
Madison, WI 53706, USA (mrculber@wisc.edu)
mRNAs that
contain a premature termination codon often fail to produce truncated proteins
because they are targeted for rapid turnover by nonsense-mediated mRNA decay
(NMD). NMD reduces errors in gene expression through RNA surveillance and
controls the overall abundance of a substantial number of transcripts as part of
the normal repertoire of gene expression. The NMD pathway has evolved both as a
monitoring device to ensure accuracy in the proteins that are made and a
control mechanism to influence the accumulated levels of many proteins. In Saccharomyces
cerevisiae,
UPF1,
UPF2,
and UPF3,
are required for NMD. Orthologs of the UPF genes have been identified in 16
eukaryotes. The ATP-helicase domain of Upf1p is ancient and may have evolved
from an ancestor common to archea and the eukaryotes. Upf1p is the central
player in NMD. Upf1p terminates translation and triggers decapping and decay
through interactions with release factors and the decapping complex. Upf2p and
Upf3p control the activities of Upf1p by imparting substrate specificity to an
otherwise indiscriminant helicase. As components of mRNPs, Upf3p works in
concert with other proteins to mark appropriate mRNAs in the nucleus for rapid
destruction in the cytoplasm. Naturally occurring mRNAs controlled by NMD
include transcription and chromatin remodeling factors, kinetochore proteins,
and proteins that control telomere length and gene silencing.