Niels Mailand – University of Copenhagen

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CCS > Research > Niels Mailand

Niels Mailand

A key focus of the Mailand lab (The Novo Nordisk Foundation Center for Protein Research) is to understand how regulatory signaling processes promote cellular responses to DNA damage and replication stress to protect chromosome stability in mammalian cells. While much is known about the basic machinery underlying DNA repair pathways, the regulatory framework that controls and coordinates these processes is less well understood. To remedy this knowledge gap, we are combining innovative systems-wide screening approaches with focused cell- and biochemistry-based studies in order to identify and functionally characterize new factors and signaling processes that protect the integrity of the genome following genotoxic insults.

Within the Center for Chromosome Stability (CCS), our major focus is to characterize the signaling processes that enable cells to overcome replication stress, a major driver of genome instability. To understand the molecular mechanisms employed by cells to mitigate the threat posed by replication stress, we are employing cutting-edge strategies to enrich and map the factors that are recruited to the replication machinery when it encounters DNA lesions or other impediments to its continued progression. In one approach, we are using the BioID method for biotinylation and isolation of factors acting directly in the context of replication forks under various conditions. In another approach, we combine Xenopus egg extracts, a powerful cell-free system for biochemical studies of DNA transactions, with mass spectrometry to identify the spectrum of cellular proteins undergoing enrichment at the replication machinery upon DNA damage or replication stress. Using such strategies we are now able to obtain detailed, systematic insights into the signaling processes that operate directly in the context of stalled replication forks to counteract the deleterious consequences of replication stress. In collaboration with other groups within CCS, we are currently studying the functions and physiological importance of several newly identified components of replication stress-responsive pathways in protecting chromosome stability.

Recent publications:

Haahr P, Hoffmann S, Tollenaere M, Ho T, Toledo L, Mann M, Bekker-Jensen S, Raschle M, Mailand N. (2016). Activation of the ATR kinase by the RPA-binding protein ETAA1. Nature Cell Biol, 18, 1196-1207.

Hansen RK, Mund A, Poulsen SL, Sandoval M, Tsouroula K, Klement K, Tollenaere MAX, Räschle M, Soria R, Offermanns S, Worzfeld T, Grosse R, Brandt DT, Rozell B, Mann M, Cole F, Soutoglou E, Goodarzi AA, Daniel J, Mailand N, Bekker-Jensen S. (2016). SCAI promotes DNA double-strand break repair in distinct chromosomal contexts. Nature Cell Biol, 18, 1357-1366.

Saredi G, Huang H, Hammond CM, Alabert C, Bekker-Jensen S, Forne I, Reverón-Gómez N, Foster BM, Mlejnkova L, Bartke T, Mailand N, Imhof A, Patel D, Groth A. (2016). H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22 DNA repair complex. Nature 534, 714-718.

Schwertman P, Bekker-Jensen S, Mailand N. (2016). Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nature Reviews Mol Cell Biol 17, 379-394.

Hoffmann S, Smedegaard S, Nakamura K, Mortuza GB, Raschle M, Ibanez de Opakua A, Oka Y, Feng Y, Blanco FJ, Mann M, Montoya G, Groth A, Bekker-Jensen S, Mailand N. (2016). TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress. J Cell Biol 212, 63-75. 

Thorslund T, Ripplinger A, Hoffmann S, Wild T, Uckelmann M, Villumsen B, Narita T, Sixma TK, Choudhary C, Bekker-Jensen S, Mailand N. (2015). Histone H1 couples initiation and amplification of ubiquitin signaling after DNA damage. Nature 527, 389-393.

Raschle M, Smeenk G, Hansen RK, Temu T, Oka Y, Hein MY, Nagaraj N, Long DT, Walter JC, Hofmann K, Storchova Z, Bekker-Jensen S, Mailand N, Mann M. (2015). Proteomics reveals dynamic assembly of repair complexes during bypass of DNA crosslinks. Science 384, 1253671. 

Staff:
Niels Mailand, professor, group leader
Teresa Ho, postdoc
Divya Achuthankutty, PhD student