Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.

All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jennifer A Stortz, Tiago D Serafim, Sam Alsford, Jonathan Wilkes, Fernando Fernandez-Cortes, Graham Hamilton, Emma Briggs, Leandro Lemgruber, David Horn, Jeremy C Mottram, Richard McCulloch
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2017
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/423fc5b65254441ea7d9fcfdf295c690
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:423fc5b65254441ea7d9fcfdf295c690
record_format	dspace
spelling	oai:doaj.org-article:423fc5b65254441ea7d9fcfdf295c6902021-12-02T19:59:43ZGenome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.1553-73661553-737410.1371/journal.ppat.1006477https://doaj.org/article/423fc5b65254441ea7d9fcfdf295c6902017-07-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1006477https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect the life style of individual organisms. To identify genome maintenance pathways in a divergent eukaryote and important parasite, Trypanosoma brucei, we performed RNAi screens to identify genes important for survival following exposure to the alkylating agent methyl methanesulphonate. Amongst a cohort of broadly conserved and, therefore, early evolved repair pathways, we reveal multiple activities not so far examined functionally in T. brucei, including DNA polymerases, DNA helicases and chromatin factors. In addition, the screens reveal Trypanosoma- or kinetoplastid-specific repair-associated activities. We also provide focused analyses of repair-associated protein kinases and show that loss of at least nine, and potentially as many as 30 protein kinases, including a nuclear aurora kinase, sensitises T. brucei to alkylation damage. Our results demonstrate the potential for synthetic lethal genome-wide screening of gene function in T. brucei and provide an evolutionary perspective on the repair pathways that underpin effective responses to damage, with particular relevance for related kinetoplastid pathogens. By revealing that a large number of diverse T. brucei protein kinases act in the response to damage, we expand the range of eukaryotic signalling factors implicated in genome maintenance activities.Jennifer A StortzTiago D SerafimSam AlsfordJonathan WilkesFernando Fernandez-CortesGraham HamiltonEmma BriggsLeandro LemgruberDavid HornJeremy C MottramRichard McCullochPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 13, Iss 7, p e1006477 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jennifer A Stortz Tiago D Serafim Sam Alsford Jonathan Wilkes Fernando Fernandez-Cortes Graham Hamilton Emma Briggs Leandro Lemgruber David Horn Jeremy C Mottram Richard McCulloch Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
description	All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect the life style of individual organisms. To identify genome maintenance pathways in a divergent eukaryote and important parasite, Trypanosoma brucei, we performed RNAi screens to identify genes important for survival following exposure to the alkylating agent methyl methanesulphonate. Amongst a cohort of broadly conserved and, therefore, early evolved repair pathways, we reveal multiple activities not so far examined functionally in T. brucei, including DNA polymerases, DNA helicases and chromatin factors. In addition, the screens reveal Trypanosoma- or kinetoplastid-specific repair-associated activities. We also provide focused analyses of repair-associated protein kinases and show that loss of at least nine, and potentially as many as 30 protein kinases, including a nuclear aurora kinase, sensitises T. brucei to alkylation damage. Our results demonstrate the potential for synthetic lethal genome-wide screening of gene function in T. brucei and provide an evolutionary perspective on the repair pathways that underpin effective responses to damage, with particular relevance for related kinetoplastid pathogens. By revealing that a large number of diverse T. brucei protein kinases act in the response to damage, we expand the range of eukaryotic signalling factors implicated in genome maintenance activities.
format	article
author	Jennifer A Stortz Tiago D Serafim Sam Alsford Jonathan Wilkes Fernando Fernandez-Cortes Graham Hamilton Emma Briggs Leandro Lemgruber David Horn Jeremy C Mottram Richard McCulloch
author_facet	Jennifer A Stortz Tiago D Serafim Sam Alsford Jonathan Wilkes Fernando Fernandez-Cortes Graham Hamilton Emma Briggs Leandro Lemgruber David Horn Jeremy C Mottram Richard McCulloch
author_sort	Jennifer A Stortz
title	Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
title_short	Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
title_full	Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
title_fullStr	Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
title_full_unstemmed	Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.
title_sort	genome-wide and protein kinase-focused rnai screens reveal conserved and novel damage response pathways in trypanosoma brucei.
publisher	Public Library of Science (PLoS)
publishDate	2017
url	https://doaj.org/article/423fc5b65254441ea7d9fcfdf295c690
work_keys_str_mv	AT jenniferastortz genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT tiagodserafim genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT samalsford genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT jonathanwilkes genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT fernandofernandezcortes genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT grahamhamilton genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT emmabriggs genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT leandrolemgruber genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT davidhorn genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT jeremycmottram genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei AT richardmcculloch genomewideandproteinkinasefocusedrnaiscreensrevealconservedandnoveldamageresponsepathwaysintrypanosomabrucei
_version_	1718375717048156160

Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.

Ejemplares similares