Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility

ABSTRACT Living organisms are constantly exposed to DNA damage stress caused by endogenous and exogenous events. Eukaryotic cells have evolutionarily conserved DNA damage checkpoint surveillance systems. We previously reported that a unique transcription factor, Bdr1, whose expression is strongly in...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kwang-Woo Jung, Yeonseon Lee, Eun Young Huh, Soo Chan Lee, Sangyong Lim, Yong-Sun Bahn
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	C. neoformans DNA damage pathway antifungal drug susceptibility virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6613336cbe0944c0997a4d1932d046f7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6613336cbe0944c0997a4d1932d046f7
record_format	dspace
spelling	oai:doaj.org-article:6613336cbe0944c0997a4d1932d046f72021-11-15T15:55:14ZRad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility10.1128/mBio.01726-182150-7511https://doaj.org/article/6613336cbe0944c0997a4d1932d046f72019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01726-18https://doaj.org/toc/2150-7511ABSTRACT Living organisms are constantly exposed to DNA damage stress caused by endogenous and exogenous events. Eukaryotic cells have evolutionarily conserved DNA damage checkpoint surveillance systems. We previously reported that a unique transcription factor, Bdr1, whose expression is strongly induced by the protein kinase Rad53 governs DNA damage responses by controlling the expression of DNA repair genes in the basidiomycetous fungus Cryptococcus neoformans. However, the regulatory mechanism of the Rad53-dependent DNA damage signal cascade and its function in pathogenicity remain unclear. Here, we demonstrate that Rad53 is required for DNA damage response and is phosphorylated by two phosphatidylinositol 3-kinase (PI3K)-like kinases, Tel1 and Mec1, in response to DNA damage stress. Transcriptome analysis revealed that Rad53 regulates the expression of several DNA repair genes in response to gamma radiation. We found that expression of CHK1, another effector kinase involved in the DNA damage response, is regulated by Rad53 and that CHK1 deletion rendered cells highly susceptible to DNA damage stress. Nevertheless, BDR1 expression is regulated by Rad53, but not Chk1, indicating that DNA damage signal cascades mediated by Rad53 and Chk1 exhibit redundant and distinct functions. We found that perturbation of both RAD53 and CHK1 attenuated the virulence of C. neoformans, perhaps by promoting phagosome maturation within macrophage, reducing melanin production, and increasing susceptibility to oxidative stresses. Furthermore, deletion of both RAD53 and CHK1 increased susceptibility to certain antifungal drugs such as amphotericin B. This report provides insight into the regulatory mechanism of fungal DNA damage repair systems and their functional relationship with fungal virulence and antifungal drug susceptibility. IMPORTANCE Genome instability is detrimental for living things because it induces genetic disorder diseases and transfers incorrect genome information to descendants. Therefore, living organisms have evolutionarily conserved signaling networks to sense and repair DNA damage. However, how the DNA damage response pathway is regulated for maintaining the genome integrity of fungal pathogens and how this contributes to their pathogenicity remain elusive. In this study, we investigated the DNA damage response pathway in the basidiomycete pathogen Cryptococcus neoformans, which causes life-threatening meningoencephalitis in immunocompromised individuals, with an average of 223,100 infections leading to 181,100 deaths reported annually. Here, we found that perturbation of Rad53- and Chk1-dependent DNA damage response pathways attenuated the virulence of C. neoformans and increased its susceptibility to certain antifungal drugs, such as amphotericin B and flucytosine. Therefore, our work paves the way to understanding the important role of human fungal DNA damage networks in pathogenesis and antifungal drug susceptibility.Kwang-Woo JungYeonseon LeeEun Young HuhSoo Chan LeeSangyong LimYong-Sun BahnAmerican Society for MicrobiologyarticleC. neoformansDNA damage pathwayantifungal drug susceptibilityvirulenceMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	C. neoformans DNA damage pathway antifungal drug susceptibility virulence Microbiology QR1-502
spellingShingle	C. neoformans DNA damage pathway antifungal drug susceptibility virulence Microbiology QR1-502 Kwang-Woo Jung Yeonseon Lee Eun Young Huh Soo Chan Lee Sangyong Lim Yong-Sun Bahn Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
description	ABSTRACT Living organisms are constantly exposed to DNA damage stress caused by endogenous and exogenous events. Eukaryotic cells have evolutionarily conserved DNA damage checkpoint surveillance systems. We previously reported that a unique transcription factor, Bdr1, whose expression is strongly induced by the protein kinase Rad53 governs DNA damage responses by controlling the expression of DNA repair genes in the basidiomycetous fungus Cryptococcus neoformans. However, the regulatory mechanism of the Rad53-dependent DNA damage signal cascade and its function in pathogenicity remain unclear. Here, we demonstrate that Rad53 is required for DNA damage response and is phosphorylated by two phosphatidylinositol 3-kinase (PI3K)-like kinases, Tel1 and Mec1, in response to DNA damage stress. Transcriptome analysis revealed that Rad53 regulates the expression of several DNA repair genes in response to gamma radiation. We found that expression of CHK1, another effector kinase involved in the DNA damage response, is regulated by Rad53 and that CHK1 deletion rendered cells highly susceptible to DNA damage stress. Nevertheless, BDR1 expression is regulated by Rad53, but not Chk1, indicating that DNA damage signal cascades mediated by Rad53 and Chk1 exhibit redundant and distinct functions. We found that perturbation of both RAD53 and CHK1 attenuated the virulence of C. neoformans, perhaps by promoting phagosome maturation within macrophage, reducing melanin production, and increasing susceptibility to oxidative stresses. Furthermore, deletion of both RAD53 and CHK1 increased susceptibility to certain antifungal drugs such as amphotericin B. This report provides insight into the regulatory mechanism of fungal DNA damage repair systems and their functional relationship with fungal virulence and antifungal drug susceptibility. IMPORTANCE Genome instability is detrimental for living things because it induces genetic disorder diseases and transfers incorrect genome information to descendants. Therefore, living organisms have evolutionarily conserved signaling networks to sense and repair DNA damage. However, how the DNA damage response pathway is regulated for maintaining the genome integrity of fungal pathogens and how this contributes to their pathogenicity remain elusive. In this study, we investigated the DNA damage response pathway in the basidiomycete pathogen Cryptococcus neoformans, which causes life-threatening meningoencephalitis in immunocompromised individuals, with an average of 223,100 infections leading to 181,100 deaths reported annually. Here, we found that perturbation of Rad53- and Chk1-dependent DNA damage response pathways attenuated the virulence of C. neoformans and increased its susceptibility to certain antifungal drugs, such as amphotericin B and flucytosine. Therefore, our work paves the way to understanding the important role of human fungal DNA damage networks in pathogenesis and antifungal drug susceptibility.
format	article
author	Kwang-Woo Jung Yeonseon Lee Eun Young Huh Soo Chan Lee Sangyong Lim Yong-Sun Bahn
author_facet	Kwang-Woo Jung Yeonseon Lee Eun Young Huh Soo Chan Lee Sangyong Lim Yong-Sun Bahn
author_sort	Kwang-Woo Jung
title	Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
title_short	Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
title_full	Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
title_fullStr	Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
title_full_unstemmed	Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
title_sort	rad53- and chk1-dependent dna damage response pathways cooperatively promote fungal pathogenesis and modulate antifungal drug susceptibility
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/6613336cbe0944c0997a4d1932d046f7
work_keys_str_mv	AT kwangwoojung rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility AT yeonseonlee rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility AT eunyounghuh rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility AT soochanlee rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility AT sangyonglim rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility AT yongsunbahn rad53andchk1dependentdnadamageresponsepathwayscooperativelypromotefungalpathogenesisandmodulateantifungaldrugsusceptibility
_version_	1718427222101983232

Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility

Ejemplares similares