The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells
Molecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be dependent on cha...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/7/864 |
| _version_ | 1797407403404165120 |
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| author | Siddhi Omkar Tasaduq H. Wani Bo Zheng Megan M. Mitchem Andrew W. Truman |
| author_facet | Siddhi Omkar Tasaduq H. Wani Bo Zheng Megan M. Mitchem Andrew W. Truman |
| author_sort | Siddhi Omkar |
| collection | DOAJ |
| description | Molecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be dependent on chaperone activity. In this study, we demonstrate that the budding yeast Apn2 exonuclease interacts with molecular chaperones Ssa1 and Hsp82 and the co-chaperone Ydj1. Although Apn2 does not display a binding preference for any specific cytosolic Hsp70 or Hsp90 paralog, Ssa1 is unable to support Apn2 stability when present as the sole Ssa in the cell. Demonstrating conservation of this mechanism, the exonuclease APE2 also binds to Hsp70 and Hsp90 in mammalian cells. Inhibition of chaperone function via specific small molecule inhibitors results in a rapid loss of APE2 in a range of cancer cell lines. Taken together, these data identify APE2 and Apn2 as clients of the chaperone system in yeast and mammalian cells and suggest that chaperone inhibition may form the basis of novel anticancer therapies that target APE2-mediated processes. |
| first_indexed | 2024-03-09T03:40:55Z |
| format | Article |
| id | doaj.art-e5fc1fdeed1941f3ac2fb2a6a48dd9d8 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:40:55Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e5fc1fdeed1941f3ac2fb2a6a48dd9d82023-12-03T14:41:43ZengMDPI AGBiomolecules2218-273X2022-06-0112786410.3390/biom12070864The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian CellsSiddhi Omkar0Tasaduq H. Wani1Bo Zheng2Megan M. Mitchem3Andrew W. Truman4Department of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223, USADepartment of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223, USADepartment of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223, USADepartment of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223, USADepartment of Biological Sciences, The University of North Carolina at Charlotte, Charlotte, NC 28223, USAMolecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be dependent on chaperone activity. In this study, we demonstrate that the budding yeast Apn2 exonuclease interacts with molecular chaperones Ssa1 and Hsp82 and the co-chaperone Ydj1. Although Apn2 does not display a binding preference for any specific cytosolic Hsp70 or Hsp90 paralog, Ssa1 is unable to support Apn2 stability when present as the sole Ssa in the cell. Demonstrating conservation of this mechanism, the exonuclease APE2 also binds to Hsp70 and Hsp90 in mammalian cells. Inhibition of chaperone function via specific small molecule inhibitors results in a rapid loss of APE2 in a range of cancer cell lines. Taken together, these data identify APE2 and Apn2 as clients of the chaperone system in yeast and mammalian cells and suggest that chaperone inhibition may form the basis of novel anticancer therapies that target APE2-mediated processes.https://www.mdpi.com/2218-273X/12/7/864Hsp70Hsp90APE2Apn2cancerchaperone inhibition |
| spellingShingle | Siddhi Omkar Tasaduq H. Wani Bo Zheng Megan M. Mitchem Andrew W. Truman The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells Biomolecules Hsp70 Hsp90 APE2 Apn2 cancer chaperone inhibition |
| title | The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells |
| title_full | The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells |
| title_fullStr | The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells |
| title_full_unstemmed | The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells |
| title_short | The APE2 Exonuclease Is a Client of the Hsp70–Hsp90 Axis in Yeast and Mammalian Cells |
| title_sort | ape2 exonuclease is a client of the hsp70 hsp90 axis in yeast and mammalian cells |
| topic | Hsp70 Hsp90 APE2 Apn2 cancer chaperone inhibition |
| url | https://www.mdpi.com/2218-273X/12/7/864 |
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