SUMO signaling in genome stability maintenance

Location: Small Lecture Theatre: Medical Sciences Institute, SLS 

Hosts: John Rouse and Karim Labib

MRC Protein Phosphorylation and Ubiquitylation Seminar

Abstract

Signaling via the polypeptide SUMO is a crucial mediator of cellular stress responses and has been implicated in multiple aspects of genome stability maintenance. My presentation will focus on our recent efforts to understand the mechanisms and function of SUMOylation in the repair of cytotoxic DNA-protein crosslinks (DPCs) in vertebrates. I will also describe our ongoing CRISPR/Cas9 screening-based work to elucidate what constitutes the essential roles of SUMOylation in underpinning chromosomal stability and cell proliferation. 

Biosketch

Niels Mailand’s group seeks to understand how signaling processes driven by ubiquitin, SUMO and other post-translational protein modifications (PTMs) orchestrate and regulate cellular responses to DNA damage and related stresses. Niels’ work combines cutting-edge proteomics- and CRISPR-based screening approaches with targeted methods within mammalian cell biology, biochemistry and advanced imaging analysis as a powerful platform for the discovery and functional exploration of cellular signaling processes that guard against pathological changes to the integrity and organization of the genome. Prior to establishing his independent group in 2010, Niels carried out his PhD and postdoctoral studies with Jiri Lukas (Danish Cancer Society, Copenhagen, Denmark) and John Diffley (Cancer Research UK, London, UK), respectively. This laid the foundation for Niels’ long-standing interest in DNA damage responses, cell cycle regulation and protein signaling mediated by ubiquitin and ubiquitin-like modifiers. Niels’ work identified and functionally characterized an extensive range of new proteins involved in DNA damage signaling and repair pathways, and the studies of Niels’ group have elucidated in mechanistic detail how signaling via ubiquitin and the related modifier protein SUMO underpins genome stability maintenance following genotoxic insults such as DNA double-strand breaks (DSBs), replication stress and, more recently, DNA-protein crosslinks (DPCs).  Niels was elected to the EMBO Young Investigator Programme in 2013 and the work of his group has been supported by the Novo Nordisk Foundation and the European Research Council (ERC). 

Recent publications

Shearer RF, Typas D, Coscia F, Schovsbo S, Kruse T, Mund A, Mailand N. 

K27-linked ubiquitylation promotes p97 substrate processing and is essential for cell proliferation. 

EMBO J. (2022) 41:e110145. doi: 10.15252/embj.2021110145 

Liu JCY, Kühbacher U, Larsen NB, Borgermann N, Garvanska DH, Hendriks IA, Ackermann L, Haahr P, Gallina I, Guérillon C, Branigan E, Hay RT, Azuma Y, Nielsen ML, Duxin JP, Mailand N. 

Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. 

EMBO J. (2021) 40:e107413. doi: 10.15252/embj.2020107413. 

Gallina I, Hendriks IA, Hoffmann S, Larsen NB, Johansen J, Colding-Christensen CS, Schubert L, Sellés-Baiget S, Fábián Z, Kühbacher U, Gao AO, Räschle M, Rasmussen S, Nielsen ML, Mailand N, Duxin JP. 

The ubiquitin ligase RFWD3 is required for translesion DNA synthesis. 

Mol Cell (2021) 81, 442-458