ADD domain added new binding partners for the nuclear hub protein ATRX

Abstract

ATRX is a large, multi-domain nuclear protein that functions as a crucial ATP-dependent chromatin remodeler, transcriptional regulator, and guardian of telomeric and genomic integrity. As a member of the SWI/SNF family of chromatin remodeling proteins, a primary and well-defined function of ATRX is to facilitate the replication-independent deposition of the histone variant H3.3 at specific genomic loci, predominantly repetitive sequences such as telomeres, pericentromeric heterochromatin, and ribosomal DNA (rDNA). Mutations in the ATRX gene are associated with a severe X-linked neurodevelopmental disorder and alpha-thalassemia. Moreover, ATRX dysfunction can lead to genomic instability, contributing to the development and progression of various cancers, including gliomas and pancreatic neuroendocrine tumors (PanNETs). ATRX orchestrates chromatin dynamics through its modular domains. Its N-terminal ADD domain and a PxVxL-like motif recognize histone H3K9me3 and interact with the heterochromatin-binding protein HP1α, respectively. Collaborating with the histone chaperone DAXX, ATRX then utilizes its C-terminal ATPase/Helicase domain to provide the energy needed to remodel chromatin and deposit the histone variant H3.3 into repetitive DNA regions. The Chen lab and other two groups previously elucidated the minimal elements for DAXX interaction, demonstrating that a short 1260‒1289 residues motif (DAXX-binding motif, DBM) of ATRX is solely responsible for ATRX-DAXX heterodimer formation. Beyond its role in chromatin remodeling, ATRX employs its RBR (RNA-binding region) to engage the telomeric long non-coding RNA (lncRNA) TERRA, thereby regulating TERRA-mediated R-loops and telomeric G-quadruplex (G4) structures. Interestingly, this same RBR also binds the muscle-specific lncRNA ChRO1 to coordinate constitutive heterochromatin reorganization and regulate cell differentiation. Notably, nearly half of the disease-causing mutations in ATRX, leading to a severe neurodevelopmental disorder, are clustered within the ADD domain, highlighting this relatively small domain’s critical functional importance and warranting more intense investigation. This Research Highlight discusses recent findings by Yan et al. that the histone variant macroH2A binds the ATRX ADD domain, expanding the known binding partners of this domain and providing structural insights into the interaction.

1. Introduction

ATRX is a large, multi-domain nuclear protein that functions as a crucial ATP-dependent chromatin remodeler, transcriptional regulator, and guardian of telomeric and genomic integrity [1]. As a member of the SWI/SNF family of chromatin remodeling proteins, a primary and well-defined function of ATRX is to facilitate the replication-independent deposition of the histone variant H3.3 at specific genomic loci, predominantly repetitive sequences such as telomeres, pericentromeric heterochromatin, and ribosomal DNA (rDNA). Mutations in the ATRX gene are associated with a severe X-linked neurodevelopmental disorder and alpha-thalassemia. Moreover, ATRX dysfunction can lead to genomic instability, contributing to the development and progression of various cancers, including gliomas and pancreatic neuroendocrine tumors (PanNETs) [2].

ATRX orchestrates chromatin dynamics through its modular domains. Its N-terminal ADD domain and a PxVxL-like motif recognize histone H3K9me3 and interact with the heterochromatin-binding protein HP1α, respectively. Collaborating with the histone chaperone DAXX, ATRX then utilizes its C-terminal ATPase/Helicase domain to provide the energy needed to remodel chromatin and deposit the histone variant H3.3 into repetitive DNA regions (Figure 1A) [3]. The Chen lab and other two groups previously elucidated the minimal elements for DAXX interaction, demonstrating that a short 1260‒1289 residues motif (DAXX-binding motif, DBM) of ATRX is solely responsible for ATRX-DAXX heterodimer formation [4–6]. Beyond its role in chromatin remodeling, ATRX employs its RBR (RNA-binding region) to engage the telomeric long non-coding RNA (lncRNA) TERRA, thereby regulating TERRA-mediated R-loops and telomeric G-quadruplex (G4) structures. Interestingly, this same RBR also binds the muscle-specific lncRNA ChRO1 to coordinate constitutive heterochromatin reorganization and regulate cell differentiation. Notably, nearly half of the disease-causing mutations in ATRX [7], leading to a severe neurodevelopmental disorder, are clustered within the ADD domain, highlighting this relatively small domain’s critical functional importance and warranting more intense investigation.