title: The Role of Mms22p in DNA Damage Response in Candida albicans.
abstract: To ensure correct DNA replication, eukaryotes have signaling pathways that respond to replication-associated DNA damage and trigger repair. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, a complex of proteins, including the cullin protein Rtt101p and two adapter proteins Mms22p and Mms1p, is important for proper response to replication stress. We have investigated this system in Candida albicans. In this pathogen, Mms22p is important for recovery from DNA replication damage induced by agents including methylmethane sulfonate, camptothecin, and ionizing radiation. Although no clear ortholog of Mms1p has been identified in C. albicans, loss of either Mms22p or Rtt101p generates similar damage sensitivity, consistent with a common function. In S. cerevisiae, the Mrc1p-Csm3p-Tof1p complex stabilizes stalled replication forks and activates a replication checkpoint and interacts with Mms22p. A similar complex in S. pombe, consisting of the Tof1p and Csm3p orthologs Swi1p and Swi3p, along with the fission yeast Mrc1p, genetically also interacts with Mms22p. Intriguingly in C. albicans only Mrc1p and Csm3p appear involved in damage repair, and Mms22p is required for responding to DNA damage agents in MRC1 or CSM3 conditional mutants. In C. albicans, although the loss of RAD57 greatly impairs response in the pathogen to many DNA-damaging agents, lethality due to camptothecin damage requires concomitant loss of Rad57p and Mms22p, suggesting that Mms22p is only essential for homologous recombination induced by camptothecin. These results establish that although C. albicans uses conserved cellular modules to respond to DNA damage and replication blocks, the specific details of these modules differ significantly from the S. cerevisiae model.
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China.
authors.forename: Lan
authors.identifier: http://orcid.org/0000-0002-2617-4418
authors.initials: L
authors.lastname: Yan
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China Key Laboratory of the Plateau of the Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Key Laboratory of the Plateau of the Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China.
authors.forename: Quan-zhen
authors.initials: QZ
authors.lastname: Lv
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, P.R. China.
authors.forename: Qian-yao
authors.initials: QY
authors.lastname: Ma
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec, H4B 1R6, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Côte
authors.affiliation: Department of Biology, Concordia University, Montreal, Quebec, H4B 1R6, Canada malcolm.whiteway@concordia.ca 13761571578@163.com.
authors.forename: Malcolm
authors.identifier: http://orcid.org/0000-0001-6619-7983
authors.initials: M
authors.lastname: Whiteway
authors.affiliation: Center for New Drug Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China malcolm.whiteway@concordia.ca 13761571578@163.com.
authors.forename: Yuan-ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D002176:Candida albicans / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004261:DNA Replication; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D009154:Mutation; D011485:Protein Binding; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D005656:Fungal Proteins
keywords: Candida albicans; DNA repair; genomic stability; homologous recombination; replication fork