Targeting IP6 signaling to destabilize homologous recombination proteins to overcome PARP inhibitor resistance PMID: 41935081

Experimental Techniques | Epigenetics: Understanding the Chromatin Immunoprecipitation (ChIP) Assay

2026-10-27

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

Nat Commun. 2026 Apr 4;17(1):4871. doi: 10.1038/s41467-026-71421-z.

Seon-Gyeong Lee ^# ¹ ² ³ , Yuri Seo ^# ¹ ⁴ ⁵ , Seula Jeong ^# ¹ , Yuheon Chung ¹ , Sukyeong Kong ¹ ⁶ , Minyoung Kim ¹ ⁶ , Joon Ho Rhlee ⁷ , Sihyeon Um ¹ ⁸ , Bijoy P Mathew ¹ ⁷ , Saikat Maiti ¹ ⁷ , Malleswara Rao Kuram ¹ ⁷ , Mohamed Ahmed Abozeid ¹ ⁷ , Areum Park ⁹ , Ji-Na Yoo ¹⁰ , Keon Woo Khim ² , Kyuwon Son ¹ , Enkhzul Amarsanaa ¹ , Kyunghan Kim ¹¹ ¹² , Sehoon Hong ¹¹ , Jiyeon Choi ¹¹ , In Bae Park ¹ ¹³ , Eun A Lee ¹ , Ji Hwan Jeon ⁷ , Jun Hong Park ¹ ¹⁴ , Joo Seok Han ¹ ⁸ , Chan Young Park ⁶ , Seyun Kim ¹¹ ¹² , Jang Hyun Choi ¹ ² , Sung You Hong ¹ ⁷ , Min-Duk Seo ¹⁰ , Hyuk Lee ⁹ , Joo-Yong Lee ¹⁵ , Kyungjae Myung ¹⁶ ¹⁷

Affiliations

1. Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea.
2. Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan, Korea.
3. Cas Cure Therapeutics, Magokjungang-ro 8 gil, Gangseo-gu, Seoul, Korea.
4. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea.
5. Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.
7. Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan, Korea.
8. Neuracle Genetics, Sanhakgwan 4F, 145 Anam-ro, Seongbuk-gu, Seoul, Korea.
9. Korea Research Institute of Chemical Technology, Daejeon, Korea.
10. Department of Molecular Science and Technology & College of Pharmacy, Ajou University, Suwon, Korea.
11. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
12. KAIST Stem Cell Center, KAIST, Daejeon, Korea.
13. Korea Mouse Pheotyping Center, Seoul National University, Seoul, Korea.
14. College of Veterinary Medicine, Jeonbuk ational University, Iksan, Jeonbuk, Korea.
15. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea. [email protected].
16. Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. [email protected].
17. Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea. [email protected].
# Contributed equally.

Abstract

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.