Unpicking the Roles of DNA Damage Protein Kinases in Trypanosomatids

Author(s)

Silva, Gabriel L. A. ^{[1, 2]} ; Tosi, Luiz R. O. ^[1] ; McCulloch, Richard ^[2] ; Black, Jennifer Ann ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell & Mol Biol, Ribeirao Preto - Brazil

^[2] Univ Glasgow, Inst Infect Immun & Inflammat, Welcome Ctr Integrat Parasitol, Glasgow, Lanark - Scotland

• Document type: Review article
• Source: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY; v. 9, AUG 6 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 20/01883-7 - Does signalling during DNA replication stress drive genome diversity in Leishmania?
• Grantee: Jennifer Ann Black
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/14398-0 - UK:Brazil Joint Centre Partnership in Leishmaniasis (JCPiL)
• Grantee: Angela Kaysel Cruz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/16454-9 - Characterization of the ATR kinase of Leishmania major and its role in DNA replication stress signaling
• Grantee: Gabriel Lamak Almeida da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)