A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis
Changzheng Du,
Landon J. Hansen,
Simranjit X. Singh,
Feiyifan Wang,
Ran Sun,
Casey J. Moure,
Kristen Roso,
Paula K. Greer,
Hai Yan,
Yiping He
Affiliations
Changzheng Du
The 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, China
Landon J. Hansen
The 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, USA
Simranjit X. Singh
The 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, USA
Feiyifan Wang
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA
Ran Sun
The 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, China
Casey J. Moure
The 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
Kristen Roso
The 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
Paula K. Greer
The 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
Hai Yan
The 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
Yiping He
The 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 author
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
