# ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression

## TL;DR

This study shows how ATRX mutations cause gene expression issues by creating DNA damage at a specific G-rich repeat site.

## Contribution

The paper reveals a new mechanism linking ATRX to gene regulation via G-quadruplex and R-loop mediated DNA damage.

## Key findings

- ATRX deficiency downregulates α-globin in cells with DNA damage.
- A G-rich repeat at the α-globin locus is a site of DNA damage and G-quadruplex formation.
- Deleting the G-rich repeat prevents ATRX loss effects, while inducing DNA damage reinstates them.

## Abstract

Germline mutations in the chromatin remodelling protein ATRX cause a severe developmental disorder associated with α-thalassemia. In addition, ATRX is amongst the twenty genes most frequently mutated in cancer. How ATRX mutations alter gene expression remains unclear. Using the α-globin locus as a model, here we show that ATRX deficiency downregulates α-globin in a subset of cells exhibiting DNA damage. A G-rich repeat at the α-globin locus serves as a potential site of G-quadruplex formation and DNA damage. ATRX binds this repeat co-transcriptionally, and its loss increases R-loop accumulation at this site, leading to local DNA damage and transcriptional disruption in cis. Deletion of this repeat abolishes this effect, while targeted DNA damage reinstates it. These findings reveal a mechanism linking ATRX’s role in genome stability to transcriptional regulation and uncover a molecular basis of human genetic disease mediated via a distal G-rich repeat.

ATRX mutations are associated with developmental disorders and cancer, but how they affect gene regulation is unclear. Here, the authors report that ATRX loss can perturb alpha-globin gene expression by promoting G4- and R-loop-associated DNA damage via a G-rich repeat.