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<p>Homologous recombination (HR) is crucial for maintaining genomic integrity and is tightly regulated, yet the role of ubiquitin-dependent degradation in HR proteins remains poorly understood. Through high-throughput screening for compounds that modulate the DNA replication stress response, we identify ML367 and its derivative, UNI418. Kinase profiling and detail molecular analyses reveal that UNI418 inhibits PIKfyve and PIP5K1C, reducing inositol hexaphosphate (IP<sub>6</sub>) levels and triggering Cul4A-dependent degradation of RAD51, CtIP, and CHK1. Further analysis identifies WDR5 as a DCAF protein that facilitates Cul4A-mediated proteolysis of RAD51 and CHK1. Functionally, UNI418 suppresses HR, enhances tumor sensitivity to PARP inhibitors (PARPis), and re-sensitizes PARPi-resistant tumor cells in both in vitro and in vivo xenograft models. These findings reveal a Cul4A-WDR5-dependent proteolysis pathway regulating HR protein stability via phosphatidyl inositol signaling. This mechanism offers a promising therapeutic strategy for overcoming PARPi resistance and improving combinatorial cancer treatment strategies.</p>

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Targeting IP6 signaling to destabilize homologous recombination proteins to overcome PARP inhibitor resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • Seon-gyeong Lee,
  • Yuri Seo,
  • Seula Jeong,
  • Yuheon Chung,
  • Sukyeong Kong,
  • Minyoung Kim,
  • Joon Ho Rhlee,
  • Sihyeon Um,
  • Bijoy P. Mathew,
  • Saikat Maiti,
  • Malleswara Rao Kuram,
  • Mohamed Ahmed Abozeid,
  • Areum Park,
  • Ji-Na Yoo,
  • Keon Woo Khim,
  • Kyuwon Son,
  • Enkhzul Amarsanaa,
  • Kyunghan Kim,
  • Sehoon Hong,
  • Jiyeon Choi,
  • In Bae Park,
  • Eun A. Lee,
  • Ji Hwan Jeon,
  • Jun Hong Park,
  • Joo Seok Han,
  • Chan Young Park,
  • Seyun Kim,
  • Jang Hyun Choi,
  • Sung You Hong,
  • Min-Duk Seo,
  • Hyuk Lee,
  • Joo-Yong Lee,
  • Kyungjae Myung

摘要

Homologous recombination (HR) is crucial for maintaining genomic integrity and is tightly regulated, yet the role of ubiquitin-dependent degradation in HR proteins remains poorly understood. Through high-throughput screening for compounds that modulate the DNA replication stress response, we identify ML367 and its derivative, UNI418. Kinase profiling and detail molecular analyses reveal that UNI418 inhibits PIKfyve and PIP5K1C, reducing inositol hexaphosphate (IP6) levels and triggering Cul4A-dependent degradation of RAD51, CtIP, and CHK1. Further analysis identifies WDR5 as a DCAF protein that facilitates Cul4A-mediated proteolysis of RAD51 and CHK1. Functionally, UNI418 suppresses HR, enhances tumor sensitivity to PARP inhibitors (PARPis), and re-sensitizes PARPi-resistant tumor cells in both in vitro and in vivo xenograft models. These findings reveal a Cul4A-WDR5-dependent proteolysis pathway regulating HR protein stability via phosphatidyl inositol signaling. This mechanism offers a promising therapeutic strategy for overcoming PARPi resistance and improving combinatorial cancer treatment strategies.