Mutant ATRX: uncovering a new therapeutic target for glioma

Expert Opin Ther Targets. 2018 Jul;22(7):599-613. doi: 10.1080/14728222.2018.1487953. Epub 2018 Jun 20.

Abstract

ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered: We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion: ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g. DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

Keywords: ATRX; DAXX; DNA damage; SWI/SNF2; alpha-thalassemia X-linked mutant retardation syndrome; alternative lengthening of telomeres; high-grade glioma; histone chaperone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Animals
  • Child
  • Chromatin Assembly and Disassembly / genetics
  • Epigenesis, Genetic
  • Glioma / genetics*
  • Glioma / pathology
  • Glioma / therapy
  • Humans
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / physiopathology
  • Mutation
  • Telomere Homeostasis
  • X-linked Nuclear Protein / genetics*
  • alpha-Thalassemia / genetics*
  • alpha-Thalassemia / physiopathology

Substances

  • ATRX protein, human
  • X-linked Nuclear Protein

Supplementary concepts

  • ATR-X syndrome