UPF1 involvement in nuclear functions

Abstract

UPF1 (up-frameshift 1) is a protein conserved in all eukaryotes that is necessary for NMD (nonsense-mediated mRNA decay). UPF1 mainly localizes to the cytoplasm and, via mechanisms that are linked to translation termination but not yet well understood, stimulates rapid destruction of mRNAs carrying a PTC (premature translation termination codon). However, some studies have indicated that in human cells UPF1 has additional roles, possibly unrelated to NMD, which are carried out in the nucleus. These might involve telomere maintenance, cell cycle progression and DNA replication. In the present paper, we review the available experimental evidence implicating UPF1 in nuclear functions. The unexpected view that emerges from this literature is that the nuclear functions primarily stem from UPF1 having an important role in DNA replication, rather than NMD affecting the expression of proteins involved in these processes. Our bioinformatics survey of the interaction network of UPF1 with other human proteins, however, highlights that UPF1 also interacts with proteins associated with nuclear RNA degradation and transcription termination; therefore suggesting involvement in processes that could also impinge on DNA replication indirectly.

Unique Aspects of Plant Nonsense-Mediated mRNA Decay

“…The affected animals had defects in multiple developmental processes, and it is currently unknown whether animal death resulted from a single or a combination of impaired processes. Moreover, in addition to their role in NMD, some NMD factors play a role in other cellular processes, including DNA synthesis, cell cycle progression, and the maintenance of telomeres (reviewed in [95,96]). Disruption of such NMD-unrelated processes could also contribute to animal lethality.…”

In VivoDetermination of Direct Targets of the Nonsense-Mediated Decay Pathway inDrosophila

“…In this scenario, loss of NMD factors results in reduced transcription of these NMD targets, compensating for the concurrent increase in mRNA stability, which results in unchanged steady-state expression levels. A number of NMD factors are known to shuttle between the cytoplasm and the nucleus (Isken and Maquat 2008), and some are known to have nuclear functions (Brogna 1999; de Turris et al 2011; Varsally and Brogna 2012). …”

Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay

“…Efficient depletion or elimination of several NMD components results in multisystemic developmental abnormalities and eventual embryonic lethality in worms, zebrafish, flies, and mice, which may be attributable to NMD or non-NMD functions (for review, see Hwang and Maquat 2011;Varsally and Brogna 2012). Notably, examination of available ChIP data revealed that 116 genes that were derepressed following NMD-inhibition have been previously identified as targets of the POU5F1 (also known as OCT4) TF, a master regulator of pluripotency (P < 0.005 by hypergeometric test) (Supplemental Table S3; Kim et al 2008).…”