Unpicking the Roles of DNA Damage Protein Kinases in Trypanosomatids

Abstract

To preserve genome integrity when faced with DNA lesions, cells activate and coordinate a multitude of DNA repair pathways to ensure timely error correction or tolerance, collectively called the DNA damage response (DDR). These interconnecting damage response pathways are molecular signal relays, with protein kinases (PKs) at the pinnacle. Focused efforts in model eukaryotes have revealed intricate aspects of DNA repair PK function, including how they direct DDR pathways and how repair reactions connect to wider cellular processes, including DNA replication and transcription. The Kinetoplastidae, including many parasites like Trypanosoma spp. and Leishmania spp. (causative agents of debilitating, neglected tropical infections), exhibit peculiarities in several core biological processes, including the predominance of multigenic transcription and the streamlining or repurposing of DNA repair pathways, such as the loss of non-homologous end joining and novel operation of nucleotide excision repair (NER). Very recent studies have implicated ATR and ATM kinases in the DDR of kinetoplastid parasites, whereas DNA-dependent protein kinase (DNA-PKcs) displays uncertain conservation, questioning what functions it fulfills. The wide range of genetic manipulation approaches in these organisms presents an opportunity to investigate DNA repair kinase roles in kinetoplastids and to ask if further kinases are involved. Furthermore, the availability of kinase inhibitory compounds, targeting numerous eukaryotic PKs, could allow us to test the suitability of DNA repair PKs as novel chemotherapeutic targets. Here, we will review recent advances in the study of trypanosomatid DNA repair kinases.

Plant PAXX has an XLF-like function and stimulates DNA end-joining by the Ku-DNA ligase IV-XRCC4 complex

“…Apart from Ku70/80 and DNA-PKcs, core NHEJ proteins are absent in most organisms belonging to the excavata group. A recent evolutional analysis of DNA-PKcs identified its orthologs in a wide range of eukaryotes including Naegleria gruberi (Lees-Miller et al, 2021) and Leishmania major (Silva et al, 2021). In addition, we found that Trypanosoma cruzi has a putative DNA-PKcs ortholog that does not have the FAT, kinase and FATC domains but the heat-repeat domain, of which fold is predicted to be similar to that of human DNA-PKcs (Figure 1; Figure S1b).…”

Plant PAXX has an XLF‐like function and stimulates DNA end joining by the Ku‐DNA ligase IV/XRCC4 complex

“…Apart from Ku70/80 and DNA‐PKcs, core NHEJ proteins are absent in most organisms belonging to the excavata group. A recent evolutional analysis of DNA‐PKcs identified its orthologs in a wide range of eukaryotes including Naegleria gruberi (Lees‐Miller et al., 2021) and Leishmania major (Silva et al., 2021). In addition, we found that Trypanosoma cruzi has a putative DNA‐PKcs ortholog that does not have the FAT, kinase and FATC domains but the heat‐repeat domain, of which fold is predicted to be similar to that of human DNA‐PKcs (Figure 1; Figure S1b).…”