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Transcriptomic response of yeast cells to ATX1 deletion under different copper levels.

Cankorur-Cetinkaya A, Eraslan S, Kirdar B - BMC Genomics (2016)

Bottom Line: ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment.The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation.The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Faculty of Engineering, Bogazici University, 34342, Istanbul, Turkey. ayca.cankorur@boun.edu.tr.

ABSTRACT

Background: Iron and copper homeostatic pathways are tightly linked since copper is required as a cofactor for high affinity iron transport. Atx1p plays an important role in the intracellular copper transport as a copper chaperone transferring copper from the transporters to Ccc2p for its subsequent insertion into Fet3p, which is required for high affinity iron transport.

Results: In this study, genome-wide transcriptional landscape of ATX1 deletants grown in media either lacking copper or having excess copper was investigated. ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment. The present study revealed that iron ion homeostasis was not significantly affected by the absence of ATX1 either at the transcriptional or metabolic levels, suggesting other possible roles for Atx1p in addition to its function as a chaperone in copper-dependent iron absorption. The analysis of the transcriptomic response of atx1∆/atx1∆ and its integration with the genetic interaction network highlighted for the first time, the possible role of ATX1 in cell cycle regulation, likewise its mammalian counterpart ATOX1, which was reported to play an important role in the copper-stimulated proliferation of non-small lung cancer cells.

Conclusions: The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation. The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Integrative Analyses of Transcriptional Response to ATX1 deletion with Genetic Interaction Network. This figure represents the connected component of the genetic interaction network between the genes responsive to the deletion of ATX1 either dependent or independent of the copper level. a The genes were grouped according to their distance to ATX1 and enriched GO biological process terms among each level of neighbours were indicated. b The paths connecting ATX1 and GAR1 are represented. The edges between the genes were coloured according to the type of the genetic interaction between the genes. Blue represents the negative genetic, purple represents the synthetic growth defect, green represents the positive genetic, red represents the synthetic lethal, pink represents the dosage lethality, and turquois represents the synthetic rescue. The genes that were either down- or up-regulated in the ATX1 delatants were also indicated in the figure. The genes without any indication are the ones which gave opposite response to the gene deletion under different copper levels
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Fig3: Integrative Analyses of Transcriptional Response to ATX1 deletion with Genetic Interaction Network. This figure represents the connected component of the genetic interaction network between the genes responsive to the deletion of ATX1 either dependent or independent of the copper level. a The genes were grouped according to their distance to ATX1 and enriched GO biological process terms among each level of neighbours were indicated. b The paths connecting ATX1 and GAR1 are represented. The edges between the genes were coloured according to the type of the genetic interaction between the genes. Blue represents the negative genetic, purple represents the synthetic growth defect, green represents the positive genetic, red represents the synthetic lethal, pink represents the dosage lethality, and turquois represents the synthetic rescue. The genes that were either down- or up-regulated in the ATX1 delatants were also indicated in the figure. The genes without any indication are the ones which gave opposite response to the gene deletion under different copper levels

Mentions: In order to identify the relation between ATX1 and the other genes, the nodes in the network were grouped according to their distance to ATX1 (Fig. 3a). This grouping revealed that the longest path between the ATX1 and any gene in the network was 7. ATX1 has direct genetic interactions with four genes; IXR1, which encodes HMG-domain protein which binds the major DNA adducts of the antitumor drug cisplatin [26], TIR3, which encodes a cell wall mannoprotein, RTC2, which encodes putative vacuolar membrane transporter for cationic amino acids, and HUR1, which encodes a protein with unknown function, mutations of which reported to show decreased metal resistance and increased ionic stress resistance [27]. 36 genes, which were second neighbours of ATX1, were found to be significantly enriched with the regulation of transcription from RNA polymerase II promoter GO biological process terms. 161 genes, which were third neighbours of ATX1, were identified significantly enriched with cell cycle GO biological process term. There were 166 genes, which were the forth neighbour of ATX1 but they were not significantly enriched with any GO biological process term. There were 48 genes, which were the fifth neighbours of the ATX1 and they were significantly enriched with cellular amino acid catabolic GO biological process term. There were five genes, which were connected to ATX1 as the 6th neighbours. GAR1, which encodes a protein involved in the modification and cleavage of the 18S pre-rRNA, was located at the longest distance to ATX1.Fig. 3


Transcriptomic response of yeast cells to ATX1 deletion under different copper levels.

Cankorur-Cetinkaya A, Eraslan S, Kirdar B - BMC Genomics (2016)

Integrative Analyses of Transcriptional Response to ATX1 deletion with Genetic Interaction Network. This figure represents the connected component of the genetic interaction network between the genes responsive to the deletion of ATX1 either dependent or independent of the copper level. a The genes were grouped according to their distance to ATX1 and enriched GO biological process terms among each level of neighbours were indicated. b The paths connecting ATX1 and GAR1 are represented. The edges between the genes were coloured according to the type of the genetic interaction between the genes. Blue represents the negative genetic, purple represents the synthetic growth defect, green represents the positive genetic, red represents the synthetic lethal, pink represents the dosage lethality, and turquois represents the synthetic rescue. The genes that were either down- or up-regulated in the ATX1 delatants were also indicated in the figure. The genes without any indication are the ones which gave opposite response to the gene deletion under different copper levels
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940881&req=5

Fig3: Integrative Analyses of Transcriptional Response to ATX1 deletion with Genetic Interaction Network. This figure represents the connected component of the genetic interaction network between the genes responsive to the deletion of ATX1 either dependent or independent of the copper level. a The genes were grouped according to their distance to ATX1 and enriched GO biological process terms among each level of neighbours were indicated. b The paths connecting ATX1 and GAR1 are represented. The edges between the genes were coloured according to the type of the genetic interaction between the genes. Blue represents the negative genetic, purple represents the synthetic growth defect, green represents the positive genetic, red represents the synthetic lethal, pink represents the dosage lethality, and turquois represents the synthetic rescue. The genes that were either down- or up-regulated in the ATX1 delatants were also indicated in the figure. The genes without any indication are the ones which gave opposite response to the gene deletion under different copper levels
Mentions: In order to identify the relation between ATX1 and the other genes, the nodes in the network were grouped according to their distance to ATX1 (Fig. 3a). This grouping revealed that the longest path between the ATX1 and any gene in the network was 7. ATX1 has direct genetic interactions with four genes; IXR1, which encodes HMG-domain protein which binds the major DNA adducts of the antitumor drug cisplatin [26], TIR3, which encodes a cell wall mannoprotein, RTC2, which encodes putative vacuolar membrane transporter for cationic amino acids, and HUR1, which encodes a protein with unknown function, mutations of which reported to show decreased metal resistance and increased ionic stress resistance [27]. 36 genes, which were second neighbours of ATX1, were found to be significantly enriched with the regulation of transcription from RNA polymerase II promoter GO biological process terms. 161 genes, which were third neighbours of ATX1, were identified significantly enriched with cell cycle GO biological process term. There were 166 genes, which were the forth neighbour of ATX1 but they were not significantly enriched with any GO biological process term. There were 48 genes, which were the fifth neighbours of the ATX1 and they were significantly enriched with cellular amino acid catabolic GO biological process term. There were five genes, which were connected to ATX1 as the 6th neighbours. GAR1, which encodes a protein involved in the modification and cleavage of the 18S pre-rRNA, was located at the longest distance to ATX1.Fig. 3

Bottom Line: ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment.The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation.The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Faculty of Engineering, Bogazici University, 34342, Istanbul, Turkey. ayca.cankorur@boun.edu.tr.

ABSTRACT

Background: Iron and copper homeostatic pathways are tightly linked since copper is required as a cofactor for high affinity iron transport. Atx1p plays an important role in the intracellular copper transport as a copper chaperone transferring copper from the transporters to Ccc2p for its subsequent insertion into Fet3p, which is required for high affinity iron transport.

Results: In this study, genome-wide transcriptional landscape of ATX1 deletants grown in media either lacking copper or having excess copper was investigated. ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment. The present study revealed that iron ion homeostasis was not significantly affected by the absence of ATX1 either at the transcriptional or metabolic levels, suggesting other possible roles for Atx1p in addition to its function as a chaperone in copper-dependent iron absorption. The analysis of the transcriptomic response of atx1∆/atx1∆ and its integration with the genetic interaction network highlighted for the first time, the possible role of ATX1 in cell cycle regulation, likewise its mammalian counterpart ATOX1, which was reported to play an important role in the copper-stimulated proliferation of non-small lung cancer cells.

Conclusions: The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation. The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

No MeSH data available.


Related in: MedlinePlus