Year-end Sale % OFF 
Abstract
Accurate DNA replication is critical for the maintenance of genome integrity and cellular survival. Cancer-associated alterations often involve key players of DNA replication and of the DNA damage-signalling cascade. Post-translational modifications play a fundamental role in coordinating replication and repair and central among them is ubiquitylation. We show that the E3 ligase UBR5 interacts with components of the replication fork, including the translesion synthesis (TLS) polymerase polη. Depletion of UBR5 leads to replication problems, such as slower S-phase progression, resulting in the accumulation of single stranded DNA. The effect of UBR5 knockdown is related to a mis-regulation in the pathway that controls the ubiquitylation of histone H2A (UbiH2A) and blocking this modification is sufficient to rescue the cells from replication problems. We show that the presence of polη is the main cause of replication defects and cell death when UBR5 is silenced. Finally, we unveil a novel interaction between polη and H2A suggesting that UbiH2A could be involved in polη recruitment to the chromatin and the regulation of TLS.
Highlights
DNA damage poses a great threat to DNA replication
UBR5 was previously identified as a potential interactor of DNA polymerase in a mass spectrometry screen [35], suggesting a potential role for this E3 ligase in the regulation of DNA polymerases and DNA replication
We show that the problems arising in the absence of UBR5 are directly correlated with a role of the E3 ligase in controlling the state of the chromatin at the replication fork
Summary
If left unrepaired it can lead to mutations, chromosomal aberrations and possibly cell death [1]. For this reason, DNA repair and tolerance systems have evolved to address these issues and allow safe completion of the duplication of the genome [2,3]. Among the DNA tolerance systems, DNA translesion synthesis (TLS) helps completion of DNA replication in the presence of damage by using a series of specialized DNA polymerases that can accommodate template DNA distorted by altered bases [5]. TLS is kept under tight control by various post-translational modifications of the Proliferating Cell Nuclear Antigen (PCNA), the DNA replication processivity factor, which serves as a loading platform for a number of DNA repair proteins [6]. Upon fork stalling, replicative polymerases dissociate and TLS polymerases are recruited (polymerase switching)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
