Genome Maintenance and Cancer Vulnerabilities
The group will transfer from University of Copenhagen to Danish Cancer Institute by March 1, 2025
Our research
Research in the Mailand group aims to profile and functionally characterize human gene and protein networks underlying the maintenance and integrity of the genome, a prerequisite for avoiding life-threatening diseases such as cancer that are caused by genomic alterations. With a strong focus on cutting-edge methodologies and their multifaced application in innovative experimental strategies, we combine advanced CRISPR-based genetic screening technologies (including optical pooled screening, base editing screens, etc.), functional genomics approaches, proteomics, machine-learning models, in silico protein structure modeling and targeted methods within cell and molecular biology, biochemistry and advanced imaging analysis as a powerful and versatile platform for the discovery and functional exploration of cellular machineries underpinning key dimensions of genome maintenance. In particular, we are interested in regulatory roles of signaling processes mediated by the modifier proteins ubiquitin and SUMO; the mechanisms and pathways controlling the biogenesis of histones, the fundamental building blocks of chromatin; and how genome maintenance processes are impacted by cell cycle progression, the chromatin environment and perturbations such as DNA damage and replication stress. Moreover, we employ genome-scale CRISPR screening for the discovery and mechanistic dissection of cancer-specific gene-drug and gene-gene synthetic lethality relationships, empowering the design of novel precision strategies in cancer treatment. Our scientific approach is highly interactive, and we collaborate with an extensive network of in-house, national and international experts.
Liu JCY, Ackermann L, Hoffmann S, Gal Z, Hendriks IA, Jain C, Morlot L, Tatham MH, McLelland G-L, Hay RT, Nielsen ML, Brummelkamp T, Haahr P, Mailand N: Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation. Nature Struct Mol Biol 2024;31:1355-1367
Hertz EPT, Alonso-de Vega I, Kruse T, Wang Y, Hendriks IA, Bizard AH, Eugui-Anta A, Hay RT, Nielsen ML, Nilsson J, Hickson ID, Mailand N; The SUMO-NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure. Nature Struct Mol Biol 2023; 30:1303-1313
Haahr P, Borgermann N, Guo X, Typas D, Achuthankutty D, Hoffmann S, Shearer R, Sixma T, Mailand N: ZUFSP deubiquitylates K63-linked polyubiquitin chains to promote genome stability. Mol Cell 2018; 70:165-174
Haahr P, Hoffmann S, Tollenaere M, Ho T, Toledo L, Mann M, Bekker-Jensen S, Raschle M, Mailand N: Activation of the ATR kinase by the RPA-binding protein ETAA1. Nature Cell Biol 2016; 18:1196-1207
Thorslund T, Ripplinger A, Hoffmann S, Wild T, Uckelmann M, Villumsen B, Narita T, Sixma TK, Choudhary C, Bekker-Jensen S, Mailand N: Histone H1 couples initiation and amplification of ubiquitin signaling after DNA damage. Nature 2015; 527:389-393
Group leader: Niels Mailand
Prof. Niels Mailand combines system-wide and targeted studies to understand how human proteins and their regulation by post-translational modifications promote the maintenance and integrity of the genome, which is instrumental for preventing the onset of many severe disorders associated with genomic instability. Niels carried out PhD and postdoctoral studies with world-leading scientists in this area (Jiri Lukas, Danish Cancer Society and John Diffley, Cancer Research UK, respectively), which laid the foundation for his long-standing interest in the DNA damage response and genome maintenance, chromatin biology and protein signaling mediated by ubiquitin and ubiquitin-like modifiers. In 2010, he established his independent research group at Novo Nordisk Foundation Center for Protein Research (CPR), University of Copenhagen, where he subsequently became Research Program Director in 2020. With the announced phaseout of CPR (2025-26), Niels will be moving his laboratory to the Danish Cancer Institute jointly with other CPR groups.
Among key achievements, Niels’ work identified and functionally characterized an extensive range of new proteins involved in DNA damage signaling and repair pathways, and he elucidated in mechanistic detail how signaling via ubiquitin and the related modifier protein SUMO underpins genome stability maintenance following genotoxic insults including DNA double-strand breaks, replication stress and DNA-protein crosslinks. Niels has published more than 90 peer-reviewed papers (h-index: 61 (November 2024)), is a recipient of many prestigious awards and has been elected as a member of the EMBO Young Investigator Network. He is strongly committed to training young scientists (having supervised more than 35 postdocs and PhD students) and sustainability in research (his laboratory was the first individual group at University of Copenhagen to receive the Laboratory Efficiency Assessment Framework (LEAF) GOLD certification, in 2022).
ORCID: 0000-0002-6623-709X
Staff
Contact information for all staff in GMC
Key funding
Novo Nordisk Foundation
Danish Cancer Society
Lundbeck Foundation
Independent Research Fund Denmark
Danish National Research Foundation
European Commission’s Horizon 2020 Research and Innovation Programme