Safeguarding genome integrity with small ubiquitin-like modifiers

Claessens, L.A. (2024)

Doctoral Thesis

Protein posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are critical for regulating a variety of cellular processes. Dysregulation of SUMOylation is increasingly associated with cancer and inhibitors that block SUMOylation are currently being explored as cancer treatment. We aimed to gain a better understanding of how the SUMO system governs the integrated network of nuclear signaling pathways, with a specific focus on genome maintenance. For this, we combined unbiased global mass spectrometry-based proteomics approaches with mechanistic follow-up studies. We found that the SUMO protease SENP6 maintains genome stability by ensuring the timely removal of SUMO chains on proteins involved in the response to DNA damage, affecting their localization, kinetics and nuclear condensation state. In addition, we found that noncovalent protein interactions with SUMOs mediated by SUMO-interaction motifs (SIMs) are also critical in maintaining genome stability, by facilitating the recruitment of DNA damage response proteins to the sites of damage. Lastly, we offer valuable new insights on noncovalent SUMO interactions by providing a comprehensive dataset of proteins that bind SUMO independently of the classical SUMO-SIM interaction. This suggests that the relevance of alternate modes of SUMO interactions is currently underestimated by the field and opens up new avenues for future research.

• Protein posttranslational modifications
• Small ubiquitin-like modifiers
• Genome stability
• Proteomics
• Cancer

• All authors: Claessens, L.A.
• Supervisor: Vertegaal, A.C.O.; Dijke, P. ten
• Committee: Neefjes, J.J.C.; Knipscheer, P.; Sixma, T.K.; Müller, S.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2024-06-27
• ISBN (print): 9789465060798