A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis
Summary: H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719310654 |
| _version_ | 1811209200977575936 |
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| author | Changzheng Du Landon J. Hansen Simranjit X. Singh Feiyifan Wang Ran Sun Casey J. Moure Kristen Roso Paula K. Greer Hai Yan Yiping He |
| author_facet | Changzheng Du Landon J. Hansen Simranjit X. Singh Feiyifan Wang Ran Sun Casey J. Moure Kristen Roso Paula K. Greer Hai Yan Yiping He |
| author_sort | Changzheng Du |
| collection | DOAJ |
| description | Summary: H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells. : Du et al. identify a signaling cascade that regulates the abundance of H2AX, an essential protein in mediating the DNA damage response. The study links the effect of MTAP loss, a common genetic alteration in cancers, to cancer cells’ response to DNA damage insults (e.g., genotoxic agents). Keywords: H2AX, PRMT5, RNF168, SMURF2, MTAP, glioblastoma |
| first_indexed | 2024-04-12T04:35:34Z |
| format | Article |
| id | doaj.art-459387299e6e4c179961106be258eabb |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T04:35:34Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-459387299e6e4c179961106be258eabb2022-12-22T03:47:49ZengElsevierCell Reports2211-12472019-09-01281231993211.e5A PRMT5-RNF168-SMURF2 Axis Controls H2AX ProteostasisChangzheng Du0Landon J. Hansen1Simranjit X. Singh2Feiyifan Wang3Ran Sun4Casey J. Moure5Kristen Roso6Paula K. Greer7Hai Yan8Yiping He9The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Gastrointestinal Cancer Center, Peking University Cancer Hospital, Beijing 100142, ChinaThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Pathology Graduate Program, Duke University Medical Center, Durham, NC, USADepartment of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Scientific Research Center, China-Japan Union Hospital, Jilin University, Jilin 130033, ChinaThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USAThe Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Corresponding authorSummary: H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells. : Du et al. identify a signaling cascade that regulates the abundance of H2AX, an essential protein in mediating the DNA damage response. The study links the effect of MTAP loss, a common genetic alteration in cancers, to cancer cells’ response to DNA damage insults (e.g., genotoxic agents). Keywords: H2AX, PRMT5, RNF168, SMURF2, MTAP, glioblastomahttp://www.sciencedirect.com/science/article/pii/S2211124719310654 |
| spellingShingle | Changzheng Du Landon J. Hansen Simranjit X. Singh Feiyifan Wang Ran Sun Casey J. Moure Kristen Roso Paula K. Greer Hai Yan Yiping He A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis Cell Reports |
| title | A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis |
| title_full | A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis |
| title_fullStr | A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis |
| title_full_unstemmed | A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis |
| title_short | A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis |
| title_sort | prmt5 rnf168 smurf2 axis controls h2ax proteostasis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719310654 |
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