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Popovic Lab

Institute Ruder Boskovic, Zagreb, Croatia

We investigate mechanisms of DNA-protein crosslink repair on the in vitro level and the consequences of defective DNA-protein crosslink repair on the in vivo level using CRISPR/Cas9 gene editing in zebrafish.

Popovic Lab is supported by Croatian Science Foundation Installation grant (UIP-2017-05-5258).



DNA-protein crosslink repair

We are interested in investigating the mechanisms of DNA-protein crosslink repair on the in vitro level and the consequences of defective DNA-protein crosslink repair on the in vivo level using zebrafish model.


DNA-protein crosslinks

DNA-protein crosslinks (DPCs) are a common type of DNA damage which appear when a protein forms an irreversible covalent bond with the DNA. Under physiological conditions these lesions are caused by reactive oxygen and nitrogen species, DNA helical alterations and increased aldehyde concentration due to histone demethylation, AlkB-type repair, amino acid metabolism, and lipid peroxidation. DPCs are also induced by exogenous sources such as UV light, ionizing radiation and chemotherapeutics. These lesions are very diverse because any protein in proximity to DNA can be crosslinked upon exposure to endogenous or exogenous crosslinking sources. DPCs are also intricately complex due to the diversity of crosslinking chemistries and protein sizes.

DPCs present a physical blockage to all DNA transactions: replication, transcription, recombination and repair and therefore the consequences of impaired DNA-Protein Crosslink Repair (DPCR) are severe. Considering their frequent occurrence and detrimental effect on all DNA transactions, it is not surprising that DPCs are implicated in aging, cardiovascular diseases, neurodegeneration and cancer. On a cellular level, aberrant DPC repair leads to the formation of DSBs, genomic instability and/or cell death, while on the organismal level impaired DPCR was so far shown to cause premature aging phenotypes and cancer.

Petri Dish

Proteolysis-dependent DNA-Protein Crosslink Repair

The mechanism of DNA-Protein Crosslink Repair (DPCR) is still largely unknown. The reason wasn partly due to the misconception in the field that DPCs are repaired by canonical DNA damage repair pathways, nucleotide excision repair (NER) and homologous recombination (HR). However, we and others have recently shown that DPC repair is a specialised DNA damage repair pathway which relies on the proteolytic digestion of crosslinked proteins. The central players in the pathway are the metalloproteases Wss1 in yeast and SPRTN (or DVC1) in mammals which initiate DPCR by the proteolytic cleavage of crosslinked protein, followed by the removal of the protein remnant from DNA backbone via different downstream factors. However, the discovery of the SPRTN protease only scratches the surface of this pathway and the vast majority of questions including the identity of other DPCR factors still remain to be answered. Indeed, all known DNA repair pathways involve a complex machinery consisting of numerous proteins.

Embryonic Stem Cells

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Institute Ruder Boskovic, Zagreb, Croatia

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