In mammalian cells, genetic information is stored in two locations: in the nucleus and in mitochondria. DNA in mitochondria, just like in the nucleus must be faithfully copied and mistakes lead to formation of DNA defects. Persistence of ββthese DNA defects leads to genomic instability and human diseases like cardiovascular, skeletal muscular and neurological disorders, cancer as well as normal aging process. Mitochondrial DNA (mtDNA) is subjected to a constant attack by reactive oxygen species, as a result mitochondria need a powerful repair DNA mechanism and a the DNA base excision repair (BER) pathway is a major defense mechanism against oxidative damage in human mitochondria. Mitochondrial BER enzymes form high molecular weight complexes capable of carrying out complete DNA repair called mitochondrial “repairosome”.

Although BER can be readily detected in mitochondria, the spatial-temporal organization mitochondrial repairosome and molecular mechanism by wich mtDNA is repaired is not well understood. Recently, human mitochondrial EXOG, a membrane bound 5’-exo/endonuclease, has been shown to be crucial for mitochondrial DNA repair. Depletion of EXOG causes accumulation of DNA damage in the mitochondria, but not in the nucleus, increases oxidative stress and mitochondrial dysfunction and causes cell death. It has been recently shown that, in contrast to the nuclear DNA, where DNA instability is one the hallmarks of cancer, intact mtDNA is critical for tumorigenic potential. Because preservation of mtDNA integrity in cancer cells is a key for cancer progression and EXOG emerges as potential chemosensitizing target because of its critical function in mtBER. Based on the sequence, EXOG belongs to ββα-Me nuclease family of non-specific endonucleases and contains N-terminal transmembrane domain that promotes its exclusive mitochondrial localization and confines EXOG to the inner membrane of mitochondria. Our group has recently solved the crystal structure of N-terminal truncation of EXOG and show that the enzyme is uniquely suited to perform 5’-cleaning activity that is necessary for robust DNA repair.

We currently pursue studies in two general areas (outlined below). New graduate students and postdoc candidates with interests in these areas should contact Michał.