Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role for the re-initiation of stalled viral replication forks
peer-reviewed
Erstveröffentlichung
2021-03-26Autoren
Schilling, Eva-Maria
Scherer, Myriam
Rothemund, Franziska
Stamminger, Thomas
Wissenschaftlicher Artikel
Erschienen in
PLoS Pathogens ; 17 (2021), 3. - Art.-Nr. e1009460. - ISSN 1553-7366. - eISSN 1553-7374
Link zur Originalveröffentlichung
https://dx.doi.org/10.1371/journal.ppat.1009460Institutionen
UKU. Institut für VirologieDokumentversion
Veröffentlichte Version (Verlags-PDF)Zusammenfassung
Flap endonuclease 1 (FEN1) is a member of the family of structure-specific endonucleases
implicated in regulation of DNA damage response and DNA replication. So far, knowledge
on the role of FEN1 during viral infections is limited. Previous publications indicated that poxviruses
encode a conserved protein that acts in a manner similar to FEN1 to stimulate
homologous recombination, double-strand break (DSB) repair and full-size genome formation.
Only recently, cellular FEN1 has been identified as a key component for hepatitis B
virus cccDNA formation. Here, we report on a novel functional interaction between Flap
endonuclease 1 (FEN1) and the human cytomegalovirus (HCMV) immediate early protein 1
(IE1). Our results provide evidence that IE1 manipulates FEN1 in an unprecedented manner:
we observed that direct IE1 binding does not only enhance FEN1 protein stability but
also phosphorylation at serine 187. This correlates with nucleolar exclusion of FEN1 stimulating
its DSB-generating gap endonuclease activity. Depletion of FEN1 and inhibition of its
enzymatic activity during HCMV infection significantly reduced nascent viral DNA synthesis
demonstrating a supportive role for efficient HCMV DNA replication. Furthermore, our
results indicate that FEN1 is required for the formation of DSBs during HCMV infection suggesting
that IE1 acts as viral activator of FEN1 in order to re-initiate stalled replication forks.
In summary, we propose a novel mechanism of viral FEN1 activation to overcome replication
fork barriers at difficult-to-replicate sites in viral genomes
Publikationsförderung
Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm
Wird ergänzt durch
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009460#sec031Schlagwörter
[GND]: Replikation | Phosphorylierung | Transfektion | Genomik | DNS-Reparatur[LCSH]: DNA replication | Phosphorylation | Viruses Reproduction | Transfection | Genomics | Small interfering RNA | DNA repair
[Freie Schlagwörter]: Viral replication | Immunoprecipitation
[DDC Sachgruppe]: DDC 570 / Life sciences | DDC 610 / Medicine & health
Metadata
Zur LanganzeigeDOI & Zitiervorlage
Nutzen Sie bitte diesen Identifier für Zitate & Links: http://dx.doi.org/10.18725/OPARU-37596
Schilling, Eva-Maria et al. (2021): Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role
for the re-initiation of stalled viral replication forks. Open Access Repositorium der Universität Ulm und Technischen Hochschule Ulm. http://dx.doi.org/10.18725/OPARU-37596
Verschiedene Zitierstile >