Unpicking the roles of DNA damage protein kinases in trypanosomatids

Silva, G. L.A., Tosi, L. R.O., McCulloch, R. and Black, J. A. (2021) Unpicking the roles of DNA damage protein kinases in trypanosomatids. Frontiers in Cell and Developmental Biology, 9, 636615. (doi: 10.3389/fcell.2021.636615) (PMID:34422791) (PMCID:PMC8377203)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Almedia Da Silva, Mr Gabriel and Black, Dr Jennifer and McCulloch, Professor Richard
Authors: Silva, G. L.A., Tosi, L. R.O., McCulloch, R., and Black, J. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Cell and Developmental Biology
Publisher:Frontiers Media
ISSN:2296-634X
ISSN (Online):2296-634X
Copyright Holders:Copyright © 2021 Silva, Tosi, McCulloch and Black
First Published:First published in Frontiers in Cell and Developmental Biology 9: 636615
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167605Kinase dependent control of DNA replication and repair as a drug target in Trypanosoma brucei.Richard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/K006495/1III - Parasitology
17115214CONFAP Understanding diverged genome repair and replication functions in trypanosomatid parasitesRichard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/M028909/1III - Parasitology
173173How do common and diverged features of the replicative stress response shape the biology of TriTrypRichard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/N016165/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology