Toxicity and the DNA damage response
Programme Leader: Michal Malewicz
Summary of Research Interests
High-energy radiation (e.g. ionising radiation used in radiotherapy) targets cellular components (e.g organelles, lipids, proteins and DNA) leading to toxic damage that needs to be rapidly repaired. The most severe form of cellular damage are DNA lesions inflicted by radiation and the double strand DNA breaks in particular. Unrepaired DNA damage can be very cytotoxic leading to cell/tissue death and resulting in the ultimate toxic outcomes at the organismal level. In order to manage such toxic outcomes a precise knowledge of cellular response to DNA damage is needed.
Therefore we are developing a Toxicology platform for studying toxic effects of agents that cause DNA-damage (DNA damage = MIE – molecular initiating event).
The main aim for our Toxicology platform is to:
Define pathways that control major toxic responses to radiation
Our unique approach uses proteome-wide analysis of DNA repair complexes for identification of crucial mediators governing toxic outcomes to DNA damage.
Craxton A, Somers J, Munnur D, Jukes-Jones R, Cain K and Malewicz M (2015) XLS (c9orf142) is a new component of mammalian DNA double-stranded break repair. Cell Death and Differentiation – (22); 890-897 (Open Access). http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd201522a.html *
* see also an editorial comment on this discovery: http://www.nature.com/cdd/journal/v22/n6/full/cdd201532a.html
Malewicz M and Perlmann T (2014) Function of transcription factors at DNA lesions in DNA repair. Exp Cell Res. 2014 Nov 15;329(1):94-100
Malewicz M, Kadkhodaei B, Kee N, Volakakis N, Hellman U, Viktorsson K, Leung CY, Chen B, Lewensohn R, van Gent DC, et al. (2011) Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes Dev 25, 2031-2040.*
*see also this article highlight in Nature Reviews Molecular Cell Biology