The Regulation of DNA Damage Tolerance by Ubiquitin and Ubiquitin-Like Modifiers

Abstract

DNA replication is an extremely complex process that needs to be executed in a highly accurate manner in order to propagate the genome. This task requires the coordination of a number of enzymatic activities and it is fragile and prone to arrest after DNA damage. DNA damage tolerance provides a last line of defense that allows completion of DNA replication in the presence of an unrepaired template. One of such mechanisms is called post-replication repair (PRR) and it is used by the cells to bypass highly distorted templates caused by damaged bases. PRR is extremely important for the cellular life and performs the bypass of the damage both in an error-free and in an error-prone manner. In light of these two possible outcomes, PRR needs to be tightly controlled in order to prevent the accumulation of mutations leading ultimately to genome instability. Post-translational modifications of PRR proteins provide the framework for this regulation with ubiquitylation and SUMOylation playing a pivotal role in choosing which pathway to activate, thus controlling the different outcomes of damage bypass. The proliferating cell nuclear antigen (PCNA), the DNA clamp for replicative polymerases, plays a central role in the regulation of damage tolerance and its modification by ubiquitin, and SUMO controls both the error-free and error-prone branches of PRR. Furthermore, a significant number of polymerases are involved in the bypass of DNA damage possess domains that can bind post-translational modifications and they are themselves target for ubiquitylation. In this review, we will focus on how ubiquitin and ubiquitin-like modifications can regulate the DNA damage tolerance systems and how they control the recruitment of different proteins to the replication fork.

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

“…DNA lesions block the progression of high fidelity replicative DNA polymerases δ and ε. To bypass them, cells employ specialized low fidelity polymerases (such as Polη, Polκ, and Rev1)–a process termed translesion synthesis (TLS) (Cipolla et al, 2016; Jansen et al, 2015). TLS is a double-edged sword: while bypass of DNA lesions allows cells to continue their proliferation program without replication arrest, low-fidelity polymerases are mutagenic on both normal and damaged DNA templates, and thus must be kept in check.…”

Protein Dynamics in Complex DNA Lesions

“…The bulky DNA lesions induced by ultraviolet (UV) radiation are processed by nucleotide excision repair (NER) (Spivak, 2015). In addition to BER and NER, cells have evolved two pathways, collectively called DNA damage tolerance (DDT), which allow the DNA replication machinery to bypass unrepaired DNA lesions (Cipolla et al, 2016). The first pathway involves error-prone translesion DNA polymerases capable of DNA synthesis through damaged template (translesion synthesis, TLS), and the second pathway is error-free and employs template switching to bypass lesions via a poorly understood mechanism (Cipolla et al, 2016).…”

“…In addition to BER and NER, cells have evolved two pathways, collectively called DNA damage tolerance (DDT), which allow the DNA replication machinery to bypass unrepaired DNA lesions (Cipolla et al, 2016). The first pathway involves error-prone translesion DNA polymerases capable of DNA synthesis through damaged template (translesion synthesis, TLS), and the second pathway is error-free and employs template switching to bypass lesions via a poorly understood mechanism (Cipolla et al, 2016). Finally, double-strand DNA breaks (DSBs) generated either during DNA replication or by external sources such as g-or UV radiation are repaired via two essential mechanisms (Ceccaldi et al, 2016;Sancar et al, 2004).…”

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways

“…Contradicting results should be considered to arrive at definitive conclusions, even when it is difficult to specify the reasons for the contradictions. For the details on the subsequent molecular mechanisms of TLS and HDR, on the significance of ubiquitination on different sites in PCNA, and on other modifications of PCNA, see the excellent recent reviews (Branzei and Psakhye 2016;Cipolla et al 2016;Garcia-Rodriguez et al 2016;Livneh et al 2016;Branzei and Szakal 2017;Kanao and Masutani 2017;Poole and Cortez 2017;Vaisman and Woodgate 2017;Leung et al 2018).…”