SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation
The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-02-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12403 |
| _version_ | 1818984024211718144 |
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| author | Ying Ma Danrui Cui Xiufang Xiong Hiroyuki Inuzuka Wenyi Wei Yi Sun Brian J. North Yongchao Zhao |
| author_facet | Ying Ma Danrui Cui Xiufang Xiong Hiroyuki Inuzuka Wenyi Wei Yi Sun Brian J. North Yongchao Zhao |
| author_sort | Ying Ma |
| collection | DOAJ |
| description | The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1‐Cullin‐F‐box (β‐TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β‐TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β‐TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation. |
| first_indexed | 2024-12-20T18:12:25Z |
| format | Article |
| id | doaj.art-a11455f9cf8e4348a93be77a7fd8550a |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-20T18:12:25Z |
| publishDate | 2019-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a11455f9cf8e4348a93be77a7fd8550a2022-12-21T19:30:27ZengWileyMolecular Oncology1574-78911878-02612019-02-0113230732110.1002/1878-0261.12403SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivationYing Ma0Danrui Cui1Xiufang Xiong2Hiroyuki Inuzuka3Wenyi Wei4Yi Sun5Brian J. North6Yongchao Zhao7Key Laboratory of Combined Multi‐Organ Transplantation Ministry of Public Health First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaKey Laboratory of Combined Multi‐Organ Transplantation Ministry of Public Health First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaInstitute of Translational Medicine Zhejiang University School of Medicine Hangzhou ChinaDepartment of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USADepartment of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USAInstitute of Translational Medicine Zhejiang University School of Medicine Hangzhou ChinaDepartment of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USAKey Laboratory of Combined Multi‐Organ Transplantation Ministry of Public Health First Affiliated Hospital Zhejiang University School of Medicine Hangzhou ChinaThe ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin–proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1‐Cullin‐F‐box (β‐TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a β‐TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for β‐TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation.https://doi.org/10.1002/1878-0261.12403AMPKCHK1glucose deprivationubiquitinationβ‐TrCP |
| spellingShingle | Ying Ma Danrui Cui Xiufang Xiong Hiroyuki Inuzuka Wenyi Wei Yi Sun Brian J. North Yongchao Zhao SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation Molecular Oncology AMPK CHK1 glucose deprivation ubiquitination β‐TrCP |
| title | SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation |
| title_full | SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation |
| title_fullStr | SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation |
| title_full_unstemmed | SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation |
| title_short | SCFβ‐TrCP ubiquitinates CHK1 in an AMPK‐dependent manner in response to glucose deprivation |
| title_sort | scfβ trcp ubiquitinates chk1 in an ampk dependent manner in response to glucose deprivation |
| topic | AMPK CHK1 glucose deprivation ubiquitination β‐TrCP |
| url | https://doi.org/10.1002/1878-0261.12403 |
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