Details

Autor(en) / Beteiligte

• Du, Changzheng
• Hansen, Landon J.
• Singh, Simranjit X.
• Wang, Feiyifan
• Sun, Ran
• Moure, Casey J.
• Roso, Kristen
• Greer, Paula K.
• Yan, Hai
• He, Yiping

Titel

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis

Ist Teil von

• Cell reports (Cambridge), 2019-09, Vol.28 (12), p.3199-3211.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. [Display omitted] •H2AX proteostasis is dynamically and conversely regulated by RNF168 and SMURF2•PRMT5 maintains the expression of RNF168, which protects H2AX from SMURF2•A disrupted PRMT5-RNF168-SMURF2 axis causes decreased H2AX levels and defective DDR 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).