Recent advances in understanding the molecular mechanisms of SLX4 recruitment in the replication stress response

Although DNA replication is tightly regulated, various impediments can stall DNA replication forks. SLX4 is a scaffold protein that responds to different types of replication stress. While the yeast Slx4 interacts mainly with structure-specific endonucleases, mammalian SLX4 collaborates with not only such nucleases but also a telomere-binding factor, a DNA helicase, and DNA repair proteins to resolve a variety of DNA intermediates arising from replication stress, thereby maintaining genome stability. Since SLX4 was identified as a causative gene for Fanconi anemia in humans, with UBZ4 domain-deleting mutation observed in a few patients, the UBZ4 domains have been highlighted as a key determinant for its recruitment to stalled forks, which has attracted considerable attention. While several studies have advanced our understanding of how SLX4 is recruited under distinct replication stresses, the precise details and context-specific regulation remain incompletely understood. In this review, we summarize what is currently known about SLX4, including its interactions with partner proteins and its roles under different types of replication stress. We also discuss the molecular basis of its recruitment to stalled forks, with particular emphasis on recent advances in understanding the contributions of the ubiquitin-binding zinc finger type 4 (UBZ4) domains and the SUMO-interacting motif (SIM) in the DNA replication stress response.