Nucleotide excision repair in Trypanosoma brucei: specialization of transcription-coupled repair due to multigenic transcription

Machado, C. R. et al. (2014) Nucleotide excision repair in Trypanosoma brucei: specialization of transcription-coupled repair due to multigenic transcription. Molecular Microbiology, 92(4), pp. 756-776. (doi:10.1111/mmi.12589) (PMID:24661334) (PMCID:PMC4138998)

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Abstract

Nucleotide excision repair (NER) is a highly conserved genome repair pathway acting on helix distorting DNA lesions. NER is divided into two sub-pathways: global genome NER (GG-NER), which is responsible for repair throughout genomes, and transcription-coupled NER (TC-NER), which acts on lesions that impede transcription. The extent of the <i>Trypanosoma brucei</i> genome that is transcribed is highly unusual, since most genes are organised in multigene transcription units, each transcribed from a single promoter. Given this transcription organisation, we have addressed the importance of NER to <i>T. brucei</i> genome maintenance by performing RNAi against all predicted contributing factors. Our results indicate that TC-NER is the main pathway of NER repair, but only CSB, XPBz and XPG contribute. Moreover, we show that UV lesions are inefficiently repaired in <i>T. brucei</i>, perhaps due to preferential use of RNA polymerase translesion synthesis. RNAi of XPC and DDB was found to be lethal, and we show that these factors act in inter-strand crosslink repair. XPD and XPB appear only to act in transcription, not repair. This work indicates that the predominance of multigenic transcription in <i>T. brucei</i> has resulted in pronounced adaptation of NER relative to the host and may be an attractive drug target.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Marcello, Dr Lucio and Mendes, Ms Isabela and Machado, Professor Carlos and McCulloch, Professor Richard and De Almeida Marques, Dr Catarina
Authors: Machado, C. R., Vieira-da-Rocha, J. P., Mendes, I. C., Rajão, M. A., Marcello, L., Bitar, M., Drummond, M. G., Grynberg, P., Oliveira, D. A.A., Marques, C., Van Houten, B., and McCulloch, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Molecular Microbiology
Publisher:Wiley
ISSN:0950-382X
ISSN (Online):1365-2958
Published Online:25 March 2014
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Molecular Microbiology 92(4):756-776
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
463981Characterisation of Orc1/Cdc6 and DNA replication initiation in Trypanosoma brucei.Richard MccullochWellcome Trust (WELLCOME)083485/Z/07/ZIII - PARASITOLOGY
371796The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)085349/Z/08/ZIII - PARASITOLOGY
371798The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)085349/B/08/ZIII - PARASITOLOGY