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<p>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.</p>

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Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Sribalasubashini Muralimanoharan,
  • Ana Corachán,
  • Azad Khosh,
  • Sierra Hathaway,
  • Natalia Garcia,
  • Susivarshini Karthigayan,
  • Claire Schenken,
  • Nicholas Stansbury,
  • Robert Schenken,
  • Maria Victoria Bariani,
  • Qiwei Yang,
  • Eloise Dray,
  • Mazhar Adli,
  • Hortensia Ferrero,
  • Ayman Al-Hendy,
  • Thomas G. Boyer

摘要

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.