| RRC ID |
90098
|
| 著者 |
Shen Y, Gupta K, Tan-Wong SM, Wen S, Fisher CA, Tamon L, Proudfoot NJ, Gibbons RJ, Higgs DR.
|
| タイトル |
ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
17(1)
|
| 公開日 |
2026-2-14
|
| DOI |
10.1038/s41467-026-69169-7
|
| PII |
10.1038/s41467-026-69169-7
|
| PMID |
41688464
|
| PMC |
PMC13018553
|
| MeSH |
DNA Damage
DNA Helicases* / genetics
DNA Helicases* / metabolism
G-Quadruplexes
Gene Expression Regulation
Genomic Instability*
Humans
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
R-Loop Structures
Transcription, Genetic
X-linked Nuclear Protein* / genetics
X-linked Nuclear Protein* / metabolism
alpha-Globins* / genetics
alpha-Globins* / metabolism
alpha-Thalassemia / genetics
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
