Abstract
Trypanosomatids are a group of primitive unicellular eukaryotes that can cause diseases in plants, insects, animals, and humans. Kinetoplast genome integrity is key to trypanosomatid cell survival and viability. Kinetoplast DNA (kDNA) is usually under attack by reactive oxygen and nitric species (ROS and RNS), damaging the DNA, and the cells must remove and repair those oxidatively generated lesions in order to survive and proliferate. Base excision repair (BER) is a well-conserved pathway for DNA repair after base damage, single-base loss, and single-strand breaks, which can arise from ROS, RSN, environmental genotoxic agents, and UV irradiation. A powerful BER system has been described in the T. cruzi kinetoplast and it is mainly carried out by DNA polymerase β (pol β) and DNA polymerase β-PAK (pol β-PAK), which are kinetoplast-located in T. cruzi as well as in other trypanosomatids. Both pol β and pol β-PAK belong to the X-family of DNA polymerases (pol X family), perform BER in trypanosomatids, and display intrinsic 5-deoxyribose phosphate (dRP) lyase and DNA polymerase activities. However, only Pol β-PAK is able to carry out trans-lesion synthesis (TLS) across 8oxoG lesions. T. cruzi cells overexpressing pol β are more resistant to ROS and are also more efficient to repair 8oxoG compared to control cells. Pol β seems to play a role in kDNA replication, since it associates with kinetoplast antipodal sites in those development stages in trypanosomatids which are competent for cell replication. ROS treatment of cells induces the overexpression of pol β, indicating that plays a role in kDNA repair. In this review, we will summarize the main features of trypanosomatid minicircle kDNA replication and the biochemical characteristics of pol β-like enzymes and their involvement in BER and kDNA replication. We also summarize key structural features of trypanosomatid pol β compared to their mammalian (human) counterpart.
Highlights
Reviewed by: Elisa Azuara-Liceaga, Universidad Autonoma de la Ciudad de Mexico, Mexico Laurence A
A powerful Base excision repair (BER) system has been described in the T. cruzi kinetoplast and it is mainly carried out by DNA polymerase b and DNA polymerase b-PAK, which are kinetoplastlocated in T. cruzi as well as in other trypanosomatids
Pol b seems to play a role in Kinetoplast DNA (kDNA) replication, since it associates with kinetoplast antipodal sites in those development stages in trypanosomatids which are competent for cell replication
Summary
The eukaryotic cell possesses mitochondrial and nuclear genomes, which can replicate and accumulate mutations. The BER system has been extensively studied in mammalian cells and starts with a DNA glycosylase that removes the damaged base, producing an apurinic/apyrimidinic site (AP site) followed by an incision of the phosphodiester backbone 5′ to the abasic site by an AP endonuclease (Krokan and Bjørås, 2013; Beard et al, 2019; Mullins et al, 2019). In the nuclei of mammalian cells, most of the DNA oxidative damage is repaired by BER, and pol b is the principal polymerase involved in this process (Krokan and Bjørås, 2013; Beard et al, 2019). We will focus mainly on the biological functions of trypanosomatid pol b and pol b-PAK
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