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Regulation of Rfa2 phosphorylation in response to genotoxic stress in Candida albicans
Gao J.2; Wang H.1; Wong A.H.-H.4; Zeng G.1; Huang Z.1; Wang Y.1; Sang J.2; Wang Y.1,3
2014-10-01
Source PublicationMolecular Microbiology
ISSN13652958 0950382X
Volume94Issue:1Pages:141-155
Abstract

Successful pathogens must be able to swiftly respond to and repair DNA damages inflicted by the host defence. The replication protein A (RPA) complex plays multiple roles in DNA damage response and is regulated by phosphorylation. However, the regulators of RPA phosphorylation remain unclear. Here, we investigated Rfa2 phosphorylation in the pathogenic fungus Candida albicans. Rfa2, a RFA subunit, is phosphorylated when DNA replication is inhibited by hydroxyurea and dephosphorylated during the recovery. By screening a phosphatase mutant library, we found that Pph3 associates with different regulatory subunits to differentially control Rfa2 dephosphorylation in stressed and unstressed cells. Site-directed mutagenesis revealed T11, S18, S29, and S30 being critical for Rfa2 phosphorylation in response to genotoxic insult. We obtained evidence that the genome integrity checkpoint kinase Mec1 and the cyclin-dependent kinase Clb2-Cdc28 mediate Rfa2 phosphorylation. Although cells expressing either a phosphomimetic or a non-phosphorylatable version of Rfa2 had defects, the latter exhibited greater sensitivity to genotoxic challenge, failure to repair DNA damages and to deactivate Rad53-mediated checkpoint pathways in a dosage-dependent manner. These mutants were also less virulent in mice. Our results provide important new insights into the regulatory mechanism and biological significance of Rfa2 phosphorylation in C. albicans.

DOI10.1111/mmi.12749
URLView the original
Indexed BySCIE
WOS Research AreaBiochemistry & Molecular Biology ; Microbiology
WOS SubjectBiochemistry & Molecular Biology ; Microbiology
WOS IDWOS:000342774700011
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Cited Times [WOS]:8   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.A-Star, Institute of Molecular and Cell Biology
2.Beijing Normal University
3.Yong Loo Lin School of Medicine
4.National University of Singapore
Recommended Citation
GB/T 7714
Gao J.,Wang H.,Wong A.H.-H.,et al. Regulation of Rfa2 phosphorylation in response to genotoxic stress in Candida albicans[J]. Molecular Microbiology,2014,94(1):141-155.
APA Gao J..,Wang H..,Wong A.H.-H..,Zeng G..,Huang Z..,...&Wang Y..(2014).Regulation of Rfa2 phosphorylation in response to genotoxic stress in Candida albicans.Molecular Microbiology,94(1),141-155.
MLA Gao J.,et al."Regulation of Rfa2 phosphorylation in response to genotoxic stress in Candida albicans".Molecular Microbiology 94.1(2014):141-155.
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