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<p>Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism active in a subset of aggressive cancers. Targeting ALT remains a therapeutic challenge due to its complexity and lack of clinically specific inhibitors. Here, we report that the natural compound Withaferin A (Wi-A) selectively impairs ALT cancer cell viability by disrupting Rad51-dependent homologous recombination (HR), a critical pathway for resolving telomeric replication stress and DNA damage in ALT cells. Comparative analysis using isogenic ALT and telomerase-positive cells revealed that Wi-A selectively downregulates PI3K/AKT signaling and induces replication stress, telomeric DNA damage, and DNA repair deficiency in ALT cells. Mechanistically, Wi-A destabilizes the Rad51 nucleoprotein filament and promotes Rad51 degradation via a RFWD3-dependent mechanism localized within ALT-associated PML bodies (APBs). Depletion of either PML or RFWD3 rescues Rad51 stability and reduces sensitivity of ALT cells to Wi-A. Together, these findings uncover a novel mechanism by which Wi-A selectively targets ALT cells through Rad51 destabilization within APBs, highlighting its potential to exploit ALT-specific vulnerabilities in telomere maintenance and DNA repair for therapeutic development.</p>

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Selective killing of ALT-cancer cells by Withaferin-A involves destabilization of Rad51 and disruption of DNA repair

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月15日

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  • Yue Yu,
  • Huayue Zhang,
  • Jia Wang,
  • Jaspreet K. Dhanjal,
  • Vidhi Malik,
  • Xiupeng Wang,
  • Sunil C. Kaul,
  • Durai Sundar,
  • Renu Wadhwa

摘要

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism active in a subset of aggressive cancers. Targeting ALT remains a therapeutic challenge due to its complexity and lack of clinically specific inhibitors. Here, we report that the natural compound Withaferin A (Wi-A) selectively impairs ALT cancer cell viability by disrupting Rad51-dependent homologous recombination (HR), a critical pathway for resolving telomeric replication stress and DNA damage in ALT cells. Comparative analysis using isogenic ALT and telomerase-positive cells revealed that Wi-A selectively downregulates PI3K/AKT signaling and induces replication stress, telomeric DNA damage, and DNA repair deficiency in ALT cells. Mechanistically, Wi-A destabilizes the Rad51 nucleoprotein filament and promotes Rad51 degradation via a RFWD3-dependent mechanism localized within ALT-associated PML bodies (APBs). Depletion of either PML or RFWD3 rescues Rad51 stability and reduces sensitivity of ALT cells to Wi-A. Together, these findings uncover a novel mechanism by which Wi-A selectively targets ALT cells through Rad51 destabilization within APBs, highlighting its potential to exploit ALT-specific vulnerabilities in telomere maintenance and DNA repair for therapeutic development.