ИСТИНА

Background. To detect DNA damage sites, which are deleterious for genome integrity, and to coordinate the repair process, eukaryotes have evolved a complex signaling network called the DNA damage response (DDR), which is principally mediated by the PI3K kinases: ATM, ATR and DNA-PK, and by the poly (ADP-ribose) polymerases. Numerous viruses induce DNA damage and genetic instability in host cells during their lifecycles, and some species also manipulate components of the DDR. Aim. Here we have attempted to provide a brief description of the interconnection between human DDR and chronic viral infections. In addition, we present the results of our studies on the involvement of components of the NHEJ repair system in HIV replication and the development of a new type of HIV-1 inhibitors. Topics overviewed. Viruses have developed various strategies to modulate DDR, and some of them use DDR for their own benefit. This is the most interesting case as it gives us some new approaches to suppressing viral infection. Polyomaviruses induce and exploit the ATM and ATR signaling pathways. Inhibition of DDR kinases reduced the DNA replication of Merkel cell polyomavirus and BK polyomavirus. DDR is also involved in the life cycle of hepatitis B virus (HBV), chronically infecting hundreds of millions of people. The reason for the chronicity is a special form of the virus genome - circular covalently closed DNA (cccDNA), remaining insensitive to antiviral therapy. Inhibition of ATR and its downstream signaling factor CHK1, but not of ATM, decreased cccDNA formation during de novo HBV infection, and intracellular cccDNA amplification. Hepatitis C virus NS3 protein is shown to interact with DNA repair factors, Werner syndrome protein and Ku70, which is a component of DNA-PK, thereby diminishing the repair efficiency of NHEJ initiated by DNA-PK. HIV-1 can exploit the NHEJ pathway for its benefit. Integration of viral DNA into a host genome, performed by viral enzyme integrase, results in single-stranded gaps in the cell DNA that must be repaired. We have analyzed the involvement of ATM, ATR and DNA-PK in the post‐integrational gap repair (PIR), and found that inhibition of DNA-PK and ATM, but not of ATR, significantly reduces the PIR efficiency. This is a rather surprising result, given that both kinases are sensors for double-strand breaks that are not formed during integration. We have shown that DNA-PK is recruited to integration sites due to binding to Ku70, and the binding disruption disturbs HIV-1 replication. Structural investigation of the binding site of these proteins allowed us to carry out molecular docking and find inhibitors of the proteins’ interaction. The leader compound is capable of suppressing PIR at micromolar concentrations. Further optimization of the inhibitor structure is undoubtedly required, but nevertheless we can talk about a new approach to HIV suppression by blocking PIR. Conclusions. Elucidation of the interactions between viruses and DDR is important both for understanding the modulation of host cell functions by these pathogens and for developing new approaches to combating viral infections. This work was supported by RSF grants 19‐74‐10021, 17-14-01107 and RFBR grant 18-29-08012.