@misc{10481/107281,
year = {2025},
month = {10},
url = {https://hdl.handle.net/10481/107281},
abstract = {Many viruses use programmed frameshifting and
stop-codon misreading to synthesize functional proteins at high
levels. The underlying mechanisms involve complex RNA
sequence/structure motifs and likely reflect optimization driven
by natural selection of inefficient, nonprogrammed processes.
Then, it follows from basic evolutionary theory that low levels of
proteins generated through gene expression errors could provide
viruses with some survival advantage. Here, we devise an
experimental demonstration of this possibility. Phage T7 recruits
the host thioredoxin as an essential processivity factor for the viral
DNA polymerase. We inserted early stop codons in the thioredoxin
gene and appended to its end the sequence encoding for a photoconvertible fluorescent protein. Virus replication was not abolished.
Single-molecule localization microscopy showed that the phage replicates even when there are only about 10 thioredoxin molecules
per host cell on average, a number orders of magnitude below typical cellular protein levels. We show that this seemingly shocking
result can be understood in molecular and evolutionary terms as a consequence of the polymerase-thioredoxin complex displaying
high kinetic stability and a long residence time, as these are required to ensure high polymerase processivity. More generally, our
demonstration that virus replication may be enabled by proteins at exceedingly low copy number suggests that viruses have access to
the wide diversity of protein variants harboring phenotypic mutations as a result of gene expression errors. This mechanism could
play a role, for instance, in cross-species transmission by enabling virus survival in the new host before adaptations appear at the
genetic level.},
organization = {MICIU/AEI/10.13039/501100011033 - ERDF/EU (PID2021-124534OB100, PID2021-125024NB-C21, SEV-2017-0712)},
organization = {Instituto de Salud Carlos III - Next Generation EU (IHRC22/00004)},
organization = {MICIU/AEI/10.13039/501100011033 - ESF Investing in your future (PRE2019-089850},
publisher = {American Chemical Society},
title = {Virus Propagation Linked to Exceedingly Rare Gene-Expression Errors: A Single-Molecule Microscopy Demonstration},
doi = {10.1021/acschembio.5c00638},
author = {Luzón Hidalgo, Raquel and D’Agostino, Gianluca and Risso, Valeria Alejandra and Delgado, Asunción and Ibarra Molero, Beatriz and Campos, Luis A. and Requejo-Isidro, Jose and Sánchez Ruiz, José Manuel},
}