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Sumoylation, a process in which SUMO (small ubiquitin like modifier) is conjugated to target proteins, emerges as a post-translational modification that mediates protein-protein interactions, protein complex assembly, and localization of target proteins. The coordinated actions of SUMO ligases, proteases, and SUMO-targeted ubiquitin ligases determine the net result of sumoylation. It is well established that sumoylation can somewhat promiscuously target proteins in groups as well as selectively target individual proteins. Through changing protein dynamics, sumoylation orchestrates multi-step processes in chromatin biology. Sumoylation influences various steps of mitosis, DNA replication, DNA damage repair, and pathways protecting chromosome integrity. This review highlights examples of SUMO-regulated nuclear processes to provide mechanistic views of sumoylation in DNA metabolism.

Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. In comparison to cdc9 single mutants, cdc9 rad59Δ double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest.