Abstract
DNA damage leads to genome instability by interfering with DNA replication. Cells possess several damage bypass pathways that mitigate the effects of DNA damage during replication. These pathways include translesion synthesis and template switching. These pathways are regulated largely through post-translational modifications of proliferating cell nuclear antigen (PCNA), an essential replication accessory factor. Mono-ubiquitylation of PCNA promotes translesion synthesis, and K63-linked poly-ubiquitylation promotes template switching. This article will discuss the mechanisms of how these post-translational modifications of PCNA control these bypass pathways from a structural and biochemical perspective. We will focus on the structure and function of the E3 ubiquitin ligases Rad18 and Rad5 that facilitate the mono-ubiquitylation and poly-ubiquitylation of PCNA, respectively. We conclude by reviewing alternative ideas about how these post-translational modifications of PCNA regulate the assembly of the multi-protein complexes that promote damage bypass pathways.
Highlights
Ionizing radiation, ultraviolet radiation, and a wide range of chemical agents damage DNA [1].The resulting DNA lesions are problematic because, if unrepaired, they can lead to mutations and chromosomal re-arrangements
We focus on translesion synthesis and template switching because these two pathways are regulated largely through post-translational modifications of proliferating cell nuclear antigen (PCNA), an essential replication accessory factor [8]
We have discussed the regulation of translesion synthesis and template switching by post-translational modifications of PCNA
Summary
Ultraviolet radiation, and a wide range of chemical agents damage DNA [1]. An underappreciated aspect of the regulation of these DNA damage bypass pathways is the role played by the E3 ubiquitin ligases that facilitate the mono-ubiquitylation and poly-ubiquitylation of PCNA. Uses the energy derived from ATP hydrolysis to reverse the replication fork [29] This leads to the stalled strand base-pairing with the newly synthesized strand on the sister duplex to form the “chicken foot” intermediate (Figure 1) [29]. It is important to note, Thesethat damage bypass pathways are largely regulated by in thewild-type ubiquitylation the fork reversal activity of Rad has not been confirmed cells. 1) DNA [8,30,31,32,33,34,35,36,37,38,39,40] These damage pathways are largely regulated by the ubiquitylation of PCNA synthesis [8]. Rad is a dual-functional enzyme, being the fork-remodeling helicase that forms the chicken foot intermediate [29]
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