Accepted_test

Apurinic/apyrimidinic endonuclease 1 and tyrosyl-DNA phosphodiesterase 1 prevent suicidal covalent DNA-protein crosslinks
by Nadejda Rechkunova | Natalia Lebedeva | Anton Endutkin | Nadezhda Dyrkheeva | Olga Lavrik | Institute of Chemical Biology and Fundamental Medicine, SB RAS | Institute of Chemical Biology and Fundamental Medicine, SB RAS | Institute of Chemical Biology and Fundamental Medicine, SB RAS | Institute of Chemical Biology and Fundamental Medicine, SB RAS | Institute of Chemical Biology and Fundamental Medicine, SB RAS
Abstract ID: 185
Event: BGRS-abstracts
Sections: [Sym 11] Section “DNA replication and repair”

DNA-protein crosslinks (DPC) are common DNA lesions induced by various external and endogenous agents. Such lesions are highly toxic due to the bulk, resulting in virtual blocking of chromatin-based processes and their inability to be repaired by canonical repair pathways. Apurinic/apyrimidinic sites (AP sites) and proteins interacting with them are one of the main sources of DPC. The aim of the work was to investigate the role of AP site processing enzymes, apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), in preventing or removing DNA-protein adducts formed in the absence of reducing agents. Such DNA-protein crosslinks can arise in cells where there are no additional reducing agents. We demonstrated that APE1 plays a critical role in preventing DPC formation in cell extracts. In contrast, TDP1 resolves some protein adducts with DNA using the same mechanism as for the removal of other groups bound to the DNA 3′-phosphate, but is unable to prevent their formation due to low AP site cleavage efficiency compared to APE1. Because APE1 activity remains high in TDP1−/− cells, DPC levels in extracts from mutant and wild-type cells were very similar and lower than in extract from APE1−/− cells.

The study is supported by the Russian Science Foundation (No. 21-64-00017).