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The DNA damage response is developmentally regulated in the African trypanosome.

Authors
  • Vieira-da-Rocha, J P1
  • Passos-Silva, D G1
  • Mendes, I C1
  • Rocha, E A1
  • Gomes, D A1
  • Machado, C R2
  • McCulloch, R3
  • 1 Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte, 30161-970, MG, Brazil. , (Brazil)
  • 2 Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte, 30161-970, MG, Brazil. Electronic address: [email protected] , (Brazil)
  • 3 The Wellcome Centre for Molecular Parasitology, College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow, G12 8TA, UK. Electronic address: [email protected]
Type
Published Article
Journal
DNA repair
Publication Date
Jan 01, 2019
Volume
73
Pages
78–90
Identifiers
DOI: 10.1016/j.dnarep.2018.11.005
PMID: 30470509
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Genomes are affected by a wide range of damage, which has resulted in the evolution of a number of widely conserved DNA repair pathways. Most of these repair reactions have been described in the African trypanosome Trypanosoma brucei, which is a genetically tractable eukaryotic microbe and important human and animal parasite, but little work has considered how the DNA damage response operates throughout the T. brucei life cycle. Using quantitative PCR we have assessed damage induction and repair in both the nuclear and mitochondrial genomes of the parasite. We show differing kinetics of repair for three forms of DNA damage, and dramatic differences in repair between replicative life cycle forms found in the testse fly midgut and the mammal. We find that mammal-infective T. brucei cells repair oxidative and crosslink-induced DNA damage more efficiently than tsetse-infective cells and, moreover, very distinct patterns of induction and repair of DNA alkylating damage in the two life cycle forms. We also reveal robust repair of DNA lesions in the highly unusual T. brucei mitochondrial genome (the kinetoplast). By examining mutants we show that nuclear alkylation damage is repaired by the concerted action of two repair pathways, and that Rad51 acts in kinetoplast repair. Finally, we correlate repair with cell cycle arrest and cell growth, revealing that induced DNA damage has strikingly differing effects on the two life cycle stages, with distinct timing of alkylation-induced cell cycle arrest and higher levels of damage induced death in mammal-infective cells. Our data reveal that T. brucei regulates the DNA damage response during its life cycle, a capacity that may be shared by many microbial pathogens that exist in variant environments during growth and transmission. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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