The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells
| Autor: | Carine Tellier-Lebegue, Nicolas Siaud, Jean-Baptiste Charbonnier, Caroline Pouvelle, Sophie Salomé-Desnoulez, Patricia Kannouche, Agathe Bacquin, Bernard S. Lopez, Mylène Perderiset |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
DNA Replication
Proteasome Endopeptidase Complex Ultraviolet Rays DNA repair Ubiquitin-Protein Ligases Amino Acid Motifs Molecular Sequence Data Eukaryotic DNA replication DNA-Directed DNA Polymerase Genome Integrity Repair and Replication DNA polymerase delta Cell Line Replication factor C Control of chromosome duplication Proliferating Cell Nuclear Antigen Genetics Humans Amino Acid Sequence Homologous Recombination DNA clamp biology DNA Helicases DNA replication Nuclear Proteins Molecular biology Chromatin Proliferating cell nuclear antigen DNA-Binding Proteins Proteolysis biology.protein DNA Damage |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | During replication, DNA damage can challenge replication fork progression and cell viability. Homologous Recombination (HR) and Translesion Synthesis (TLS) pathways appear as major players involved in the resumption and completion of DNA replication. How both pathways are coordinated in human cells to maintain genome stability is unclear. Numerous helicases are involved in HR regulation. Among them, the helicase FBH1 accumulates at sites of DNA damage and potentially constrains HR via its anti-recombinase activity. However, little is known about its regulation in vivo. Here, we report a mechanism that controls the degradation of FBH1 after DNA damage. Firstly, we found that the sliding clamp Proliferating Cell Nuclear Antigen (PCNA) is critical for FBH1 recruitment to replication factories or DNA damage sites. We then showed the anti-recombinase activity of FBH1 is partially dependent on its interaction with PCNA. Intriguingly, after its re-localization, FBH1 is targeted for degradation by the Cullin-ring ligase 4-Cdt2 (CRL4(Cdt2))-PCNA pathway via a PCNA-interacting peptide (PIP) degron. Importantly, expression of non-degradable FBH1 mutant impairs the recruitment of the TLS polymerase eta to chromatin in UV-irradiated cells. Thus, we propose that after DNA damage, FBH1 might be required to restrict HR and then degraded by the Cdt2-proteasome pathway to facilitate TLS pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|