In both normal and cancer cells numerous lethal and mutagenic DNA lesions are formed upon exposure to endogenous and exogenous damaging agents with about 20’000 lesions per cell per day, majority of which represent DNA base damages. An increase in the amount of DNA base damages has been tightly associated with aging, cancer development, as well as onset of different neurological diseases. To maintain the integrity of genetic information organized within chromatin, cells need to repair the DNA or bypass the damage by engaging specialized DNA polymerases.

The aim of our research is to identify different cellular factors that ensure efficient response to DNA damaging agents, in particular the one inducing DNA base damage. Our research focuses on exploring the importance of DNA repair proteins and specialized DNA polymerases in onset and progression of different diseases in particular developmental disorders. By using multidisciplinary approach combining various experimental techniques, including biochemistry, cell biology, genomics, proteomics, 3D cultures, imaging, shRNA/CRISPR libraries, and computational biology we aim to identify pathomechanisms that contribute to developmental disorders and could potentially serve as basis for evolution of novel therapies.

DNA base damage and chromatin integrity
Assoc. Prof. Barbara von Loon \| NTNU, Trondheim, Norway

In both normal and cancer cells numerous lethal and mutagenic DNA lesions are formed upon exposure to endogenous and exogenous damaging agents with about 20’000 lesions per cell per day, majority of which represent DNA base damages. An increase in the amount of DNA base damages has been tightly associated with aging, cancer development, as well as onset of different neurological diseases. To maintain the integrity of genetic information organized within chromatin, cells need to repair the DNA or bypass the damage by engaging specialized DNA polymerases. The aim of our research is to identify different cellular factors that ensure efficient response to DNA damaging agents, in particular the one inducing DNA base damage. Our research focuses on exploring the importance of DNA repair proteins and specialized DNA polymerases in onset and progression of different diseases in particular developmental disorders. By using multidisciplinary approach combining various experimental techniques, including biochemistry, cell biology, genomics, proteomics, 3D cultures, imaging, shRNA/CRISPR libraries, and computational biology we aim to identify pathomechanisms that contribute to developmental disorders and could potentially serve as basis for evolution of novel therapies.	Selected references van Loon B, Hübscher U, Maga G. Living on the Edge: DNA Polymerase Lambda between Genome Stability and Mutagenesis. Chem Res Toxicol. 2017 Sep 8. Crespan E, Furrer A, Rösinger M, Bertoletti F, Mentegari E, Chiapparini G, Imhof R, Ziegler N, Sturla SJ, Hübscher U, van Loon B, Maga G. Impact of ribonucleotide incorporation by DNA polymerases β and λ on oxidative base excision repair. Nat Commun. 2016 Feb 26;7:10805 Maga G, Crespan E, Markkanen E, Imhof R, Furrer A, Villani G, Hübscher U, van Loon B. DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18850-5 Furrer A, van Loon B. Handling the 3-methylcytosine lesion by six human DNA polymerases members of the B-, X- and Y-families. Nucleic Acids Res. 2014 Jan;42(1):553-66 Markkanen E, van Loon B, Ferrari E, Parsons JL, Dianov GL, Hübscher U. Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by cross-talk of phosphorylation and ubiquitination. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):437-42