C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A
Abstract C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-i...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04957-1 |
| _version_ | 1797806582803726336 |
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| author | Junyang Tan Wenjun Wang Xinjie Liu Jinhong Xu Yaping Che Yanyan Liu Jiaqiao Hu Liubing Hu Jianshuang Li Qinghua Zhou |
| author_facet | Junyang Tan Wenjun Wang Xinjie Liu Jinhong Xu Yaping Che Yanyan Liu Jiaqiao Hu Liubing Hu Jianshuang Li Qinghua Zhou |
| author_sort | Junyang Tan |
| collection | DOAJ |
| description | Abstract C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis. |
| first_indexed | 2024-03-13T06:09:27Z |
| format | Article |
| id | doaj.art-7f912610b2374390869092518b8f4b51 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-13T06:09:27Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-7f912610b2374390869092518b8f4b512023-06-11T11:22:47ZengNature PortfolioCommunications Biology2399-36422023-06-016111510.1038/s42003-023-04957-1C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1AJunyang Tan0Wenjun Wang1Xinjie Liu2Jinhong Xu3Yaping Che4Yanyan Liu5Jiaqiao Hu6Liubing Hu7Jianshuang Li8Qinghua Zhou9The Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityThe Sixth Affiliated Hospital of Jinan University, Jinan UniversityAbstract C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.https://doi.org/10.1038/s42003-023-04957-1 |
| spellingShingle | Junyang Tan Wenjun Wang Xinjie Liu Jinhong Xu Yaping Che Yanyan Liu Jiaqiao Hu Liubing Hu Jianshuang Li Qinghua Zhou C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A Communications Biology |
| title | C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A |
| title_full | C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A |
| title_fullStr | C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A |
| title_full_unstemmed | C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A |
| title_short | C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A |
| title_sort | c11orf54 promotes dna repair via blocking cma mediated degradation of hif1a |
| url | https://doi.org/10.1038/s42003-023-04957-1 |
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