The human RNA surveillance factor UPF1 is required for S phase progression and genome stability.
The eukaryotic nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs carrying premature stop codons (PTC). In humans, NMD depends on the RNA- and DNA-dependent 5'-3' helicase UPF1 and six other gene products referred to as SMG1, UPF2, UPF3, EST1A/SMG6, EST1B/SMG5, and EST1C/SMG7. The NMD machinery is also thought to coordinate mRNA nuclear export and translation and to regulate the levels of several physiologic transcripts. Furthermore, in a process named SMD, UPF1 promotes degradation of mRNAs that are bound by Staufen 1. Intriguingly, SMG1 and EST1A/SMG6 function also in DNA repair and telomere maintenance, respectively. Here, we show that UPF1 is also required for genome stability. shRNA-mediated depletion of UPF1 causes human cells to arrest early in S phase, inducing an ATR-dependent DNA-damage response. A fraction of hyperphosphorylated UPF1 associates with chromatin of unperturbed cells, and chromatin association increases in S phase and upon gamma irradiation. ATR phosphorylates UPF1 both in vitro and in vivo, and shRNA-mediated downregulation of ATR diminished the association of UPF1 with chromatin, although it did not affect NMD. Physical interaction of UPF1 with DNA polymerase delta suggests a role for human UPF1 in DNA synthesis during replication or repair.
Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), 155 Chemin des Boveresses, CH-1066 Epalinges s/Lausanne, Switzerland.
Claus M
CM
Azzalin
Joachim
J
Lingner
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D004249:DNA Damage; D004258:DNA Polymerase III; D042822:Genomic Instability / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases / Q000502:physiology*; D020871:RNA Stability / Q000502:physiology; D016196:S Phase / Q000502:physiology*
D018797:Cell Cycle Proteins; D002843:Chromatin; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004258:DNA Polymerase III; D020365:RNA Helicases