Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF

Loughran, G.; Zhdanov, A.V.; Mikhaylova, M.S.; Rozov, F.N.; Datskevich, P.N.; Kovalchuk, S.I.; Serebryakova, M.V.; Kiniry, S.J.; Michel, A.M.; O’Connor Patrick, B.F.; Papkovsky, D.B.; Atkins, J.F.; Baranov, P.V.; Shatsky, I.N.; Andreev, D.E.

Авторы: Loughran Gary, Zhdanov Alexander V., Mikhaylova Maria S., Rozov Fedor N., Datskevich Petr N., Kovalchuk Sergey I., Serebryakova Marina V., Kiniry Stephen J., Michel Audrey M., O’Connor Patrick B.F., Papkovsky Dmitri B., Atkins John F., Baranov Pavel V., Shatsky Ivan N., Andreev Dmitry E.
Журнал: Proceedings of the National Academy of Sciences of the United States of America
Том: 117
Номер: 40
Год издания: 2020
Издательство: National Academy of Sciences
Местоположение издательства: United States
Первая страница: 24936
Последняя страница: 24946
DOI: 10.1073/pnas.2001433117
Аннотация: While near-cognate codons are frequently used for translation initiation in eukaryotes, their efficiencies are usually low (<10% compared to an AUG in optimal context). Here, we describe a rare case of highly efficient near-cognate initiation. A CUG triplet located in the 5′ leader of POLG messenger RNA (mRNA) initiates almost as efficiently (∼60 to 70%) as an AUG in optimal context. This CUG directs translation of a conserved 260-triplet-long overlapping open reading frame (ORF), which we call POLGARF (POLG Alternative Reading Frame). Translation of a short upstream ORF 5′ of this CUG governs the ratio between POLG (the catalytic subunit of mitochondrial DNA polymerase) and POLGARF synthesized from a single POLG mRNA. Functional investigation of POLGARF suggests a role in extracellular signaling. While unprocessed POLGARF localizes to the nucleoli together with its interacting partner C1QBP, serum stimulation results in rapid cleavage and secretion of a POLGARF C-terminal fragment. Phylogenetic analysis shows that POLGARF evolved ∼160 million y ago due to a mammalian-wide interspersed repeat (MIR) transposition into the 5′ leader sequence of the mammalian POLG gene, which became fixed in placental mammals. This discovery of POLGARF unveils a previously undescribed mechanism of de novo protein-coding gene evolution.
Добавил в систему: Андреев Дмитрий Евгеньевич

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Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARFстатья