Lukas Group – University of Copenhagen

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CPR > Research > Protein Signaling > Lukas Group

Lukas Group - Chromosome Stability and Dynamics

 

Group Leader: Prof. Jiri Lukas

The Chromosome Stability and Dynamics Group is headed by Professor Jiri Lukas, who joined CPR in April 2012 as Executive Director.

First row from the left: Jiri Lukas, Kai Neelsen, Kumar Somyajit, Hana Sedlackova, Claudia Lukas, Fena Ochs, Maj-Britt Druedahl Rask, Julian Spies

 

The main research focus of the group are proteins and signalling pathways that regulate chromosome stability during the cell division cycle and after DNA damage, with a particular emphasis on how these mechanisms are subverted in disease.

Maintenance of chromosome stability is a formidable task considering that genomes of all organisms are continuously exposed to destabilizing assaults, both from the environment and from a variety of endogenous sources such as reactive species generated by metabolic processes, errors during DNA replication, attrition of telomeres during cellular aging, and stochastic failures of chromosome segregation. To elucidate molecular mechanisms involved in genome surveillance, we use advanced imaging and high-content microscopy to uncover new genome-maintenance pathways and study their function in a physiological environment, the nucleus of a mammalian cell. We are very excited to bring this expertise to the CPR and to combine it with equally innovative proteomic and bioinformatic approaches of the current groups. Our ambition is to harness this CPR potential to address outstanding challenges in the genome integrity field in an unprecedentedly holistic fashion. One such challenge includes chromatin modifications and their dynamics in response to genotoxic stress. Our projects dedicated to this task include: 

  • Combining high-content microscopy with RNA interference to screen for chromatin-associated genome surveillance pathways. Here we build on the successful genome wide screen that identified a novel DSB-induced histone-ubiquitylation pathway coordinated by the RNF168 ubiquitin ligase1. We are particularly interested to extend the current knowledge beyond histones and elucidate how other chromatin-associated proteins (structural and enzymatic) contribute to the choice between distinct repair and signalling pathways.
  • Elucidating molecular determinants of chromosomal fragility caused by replication stress and their impact on epigenetic memory. This project has been sparked by another recent study from our lab, which identified underreplicated DNA as a source of mitosis-born DNA breaks, associated with large segments of modified epigenome inherited by the subsequent cell generations2.
  • By combining genetic screens, high-content imaging, and mass spectrometry we aim at a systematic identification and functional characterization of regulators and substrates of posttranslational modifications (PTMs) of proteins involved in all major aspects of the DNA damage response (sensing the lesions, signalling to downstream effectors, repair reactions, chromatin remodelling). Our focus in this area is again on PTMs induced by replication stress due to its prime role as a biological barrier against cancer progression3.

 References

  1. Doil, C., et al., Cell 136, 435-446 (2009).
  2. Lukas, J., et al., Nat. Cell Biol., 13, 1161-1169 (2011).
  3. Bartkova, J., et al. Nature 434, 864-870 (2005).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

  1. Doil, C., et al., Cell 136, 435-446 (2009).
  2. Lukas, J., et al., Nat. Cell Biol., 13, 1161-1169 (2011).
  3. Bartkova, J., et al. Nature 434, 864-870 (2005).