Abstract
Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.
Highlights
Genome instability is the cause of multiple syndromes that affect normal human development and can lead to uncontrolled cell proliferation, such as in cancer [1,2,3,4,5]
This suggests that Slx5/Slx8 plays a limited role in stabilizing stalled replication forks, but the complex is engaged upon fork collapse, which is consistent with data observed for RING finger protein 4 (RNF4) [193]
They are highly specific towards their substrates and their actions are often balanced by SENPs and deubiquitylating enzyme (DUB) to regulate the half-life of small ubiquitin-like modifier (SUMO) conjugates
Summary
Genome instability is the cause of multiple syndromes that affect normal human development and can lead to uncontrolled cell proliferation, such as in cancer [1,2,3,4,5]. STUbLs are evolutionarily conserved from yeast to humans We discuss their structures and functions and highlight proteins that are direct or indirect targets of SUMO and ubiquitin regulation. Ubiquitin and SUMO are two post-translational modifications (PTMs) with increasing prominence in genome maintenance pathways [7,8,9] Both ubiquitin and SUMO attachments are catalyzed by similar enzyme cascades. The depletion of two novel really interesting new gene (RING) finger proteins 1 and 2 (Rfp and Rfp2) in Schizosaccharomyces pombe showed a similar phenotype that could be complemented with Homo sapiens RING finger protein 4 (RNF4) [25] These observations demonstrated that budding yeast Slx5/Slx, fission yeast Rfp1/Rfp2/Slx, and human RNF4 are evolutionarily conserved STUbLs [26,27,28]. We review the various processes in which these STUbLs have been implicated
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