Scholarlink

<p>Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) by transcriptional cyclin-dependent kinases (tCDKs), including CDK7, CDK9, CDK12, and CDK13. Here we find that glioblastoma stem cells (GSCs) are selectively sensitive to CDK12/CDK13 inhibition, whereas CDK7 and CDK9 inhibition cause non-specific cytotoxicity. This selective targeting halts GSC and organoid proliferation, curtails GSC invasion and suppresses tumor growth in a xenograft mouse model. In GSCs, CDK12/CDK13 inhibition leads to a rapid and genome-wide loss of serine-2 phosphorylation (pSer2) of the RNAPII CTD, abolishing transcriptional elongation and a transcriptional program sustained by key neurodevelopmental transcription factors. CDK12/CDK13 inhibition unexpectedly arrests DNA replication and replication&#xa0;fork progression in a manner distinct from the effect of inhibiting other tCDKs. This dramatic arrest precedes DNA damage response activation and cell cycle arrest, directly linking RNAPII elongation to replication&#xa0;fork dynamics and revealing a previously unrecognized dependence of DNA replication on CDK12/CDK13-RNAPII regulation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月25日

查看全文
  • Silje Lier,
  • Sara B Markusson,
  • Anja Kocijancic,
  • Martine Narum,
  • Solveig O Lund,
  • Bianka Böllering,
  • Anuja Lipsa,
  • Mirra L C Søegaard,
  • Idun D Rein,
  • Petra Santha,
  • Preeti Jain,
  • Anna Lång,
  • Emma Lång,
  • Niklas Meyer,
  • Aparajita Dutta,
  • Santosh Anand,
  • Sugith B Badugu,
  • Gaute J Nesse,
  • Rune J Forstrøm,
  • Arne Klungland,
  • Ashish Anand,
  • Steven M Pollard,
  • Stig O Bøe,
  • Johanne E Rinholm,
  • Katrin B M Frauenknecht,
  • Anna Golebiewska,
  • Simone P Niclou,
  • Kumar Somyajit,
  • Mads Lerdrup,
  • Deo P Pandey

摘要

Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) by transcriptional cyclin-dependent kinases (tCDKs), including CDK7, CDK9, CDK12, and CDK13. Here we find that glioblastoma stem cells (GSCs) are selectively sensitive to CDK12/CDK13 inhibition, whereas CDK7 and CDK9 inhibition cause non-specific cytotoxicity. This selective targeting halts GSC and organoid proliferation, curtails GSC invasion and suppresses tumor growth in a xenograft mouse model. In GSCs, CDK12/CDK13 inhibition leads to a rapid and genome-wide loss of serine-2 phosphorylation (pSer2) of the RNAPII CTD, abolishing transcriptional elongation and a transcriptional program sustained by key neurodevelopmental transcription factors. CDK12/CDK13 inhibition unexpectedly arrests DNA replication and replication fork progression in a manner distinct from the effect of inhibiting other tCDKs. This dramatic arrest precedes DNA damage response activation and cell cycle arrest, directly linking RNAPII elongation to replication fork dynamics and revealing a previously unrecognized dependence of DNA replication on CDK12/CDK13-RNAPII regulation.