Portal de investigación
Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids.
Fecha de publicación:
Fecha Ahead of Print:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Muralimanoharan S
- Khosh A
- Hathaway S
- Garcia N
- Karthigayan S
- Schenken C
- Stansbury N
- Schenken R
- Bariani MV
- Yang Q
- Dray E
- Adli M
- Al-Hendy A
- Boyer TG
Grupos
Abstract
Uterine fibroids (UFs) are the most important benign neoplastic threat to women's health worldwide, with no long-term noninvasive treatment options currently available. Among known UF driver alterations, somatic mutations in Mediator subunit MED12 are by the far the most prevalent, accounting for up to 80% of these clinically significant lesions. Although it is presently unclear how MED12 mutations trigger neoplastic transformation, MED12-mutant UFs are nonetheless characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor development. However, the basis by which MED12 mutations drive genomic instability is not known. Herein, we show that R-loop-driven replication stress in MED12-mutant UFs leads to DNA under-replication and mitotic segregation errors that drive chromosomal instability. Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment.
© 2026. The Author(s).
Datos de la publicación
- ISSN/ISSNe:
- 2045-2322, 2045-2322
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 42409897
Scientific Reports NATURE PORTFOLIO
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Cita
Muralimanoharan S,CORACHÁN A,Khosh A,Hathaway S,Garcia N,Karthigayan S,Schenken C,Stansbury N,Schenken R,Bariani MV,Yang Q,Dray E,Adli M,FERRERO H,Al A,Boyer TG. Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids. Sci. Rep.