Translesion synthesis (TLS) is the primary mechanism through which cells bypass DNA lesions during active replication and is essential for proper cell survival and genome maintenance. Recently, TLS has been implicated as a mechanism through which cancer cells develop acquired resistance to first-line genotoxic chemotherapeutics. The anti-cancer properties of these drugs (platinating agents, alkylating agents, temozolomide) is through their ability to form chemical adducts on DNA, which promotes cancer cell death. TLS in cancer cells bypasses these lesions, preventing apoptosis and resulting in a population of cancer cells with increased mutations that have the potential to develop resistance.

TLS-mediated replication bypasses multiple distinct DNA lesions through the sequential action of several TLS DNA polymerases (POLs) that work in concert with each other and the DNA sliding clamp proliferating cell nuclear antigen (PCNA). This process consists of several switching steps that are governed by specific protein-proteins interactions (PPIs) between the various POLs and between the POLs and PCNA. One such essential TLS PPI is between REV7 and REV3, two accessory subunits of POLζ. REV7 is a noncatalytic subunit of POLζ that is necessary for the recruitment of REV3, a large catalytic subunit of POLζ, to the DNA replication fork. REV7 knockout studies display cell survival suppression following cisplatin treatment (an anti-cancer platinating agent), suggesting that REV7 and it's related REV3 catalytic interaction is a promising target for chemotherapeutic sensitization.

One inhibitor of the REV7/3 interaction has been previously identified (Actis, M. et al., Bioorg Med Chem. 2016;24(18):4339-4346.). Our lab aims to continue to investigate this interaction and further identify additional therapeutic agents that sensitize cells to current chemotherapy drugs using a variety of computational, structural, and mutational studies.