Abstract
The pathogenic fungus Candida albicans switches from yeast growth to filamentous growth in response to genotoxic stresses, in which phosphoregulation of the checkpoint kinase Rad53 plays a crucial role. Here we report that the Pph3/Psy2 phosphatase complex, known to be involved in Rad53 dephosphorylation, is required for cellular responses to the DNA-damaging agent methyl methanesulfonate (MMS) but not the DNA replication inhibitor hydroxyurea (HU) in C. albicans. Deletion of either PPH3 or PSY2 resulted in enhanced filamentous growth during MMS treatment and continuous filamentous growth even after MMS removal. Moreover, during this growth, Rad53 remained hyperphosphorylated, MBF-regulated genes were downregulated, and hypha-specific genes were upregulated. We have also identified S461 and S545 on Rad53 as potential dephosphorylation sites of Pph3/Psy2 that are specifically involved in cellular responses to MMS. Therefore, our studies have identified a novel molecular mechanism mediating DNA damage response to MMS in C. albicans.
Highlights
Candida albicans is a pleiomorphic fungus that can grow in three different morphological forms: budding yeast, pseudohyphae and hyphae [1,2], rendering it an excellent model for studying cell morphogenesis [2,3,4,5]
Because filamentous growth was observed after methyl methanesulfonate (MMS) treatment, we examined the expression of several known hyphaspecific genes including HWP1, EBP1, ECE1, ALS3, SAP4 and UME6
We have previously shown that Pph3 and its regulatory subunit Psy2 are required for recovery from MMS and cisplatin treatment in C. albicans [38]
Summary
Candida albicans is a pleiomorphic fungus that can grow in three different morphological forms: budding yeast, pseudohyphae and hyphae [1,2], rendering it an excellent model for studying cell morphogenesis [2,3,4,5]. DNA damaging agents were found to cause cell cycle arrest and filamentous growth in a manner dependent on the DNA damage/replication checkpoint kinase Rad53 [21]. The yeast homolog of human Chk2 [22,23], is a Ser/Thr kinase that plays a pivotal role in G2/M checkpoint regulation by phosphorylating various substrates involved in cell cycle progression and/or DNA damage repair [24,25,26]. The N-terminal SCD is conserved in human Chk, while the C-terminal SCD is unique to the yeast homologs Several protein kinases such as Mec, Mrc and Rad9 [27,30,31,32] and phosphatases Pph and Ptc are involved in regulating Rad phosphorylation [28,33,34]. We obtained evidence on the potential sites for Pph3/Psy dephosphorylation on Rad
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