PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells

doi:10.1038/s41419-024-07009-6

	PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells
	Huang, Mei1 ; Zhu, Xiaotong1 ; Wang, Chen1 ; He, Liying1 ; Li, Lei1 ; Wang, Haopeng1,2 ; Fan, Gaofeng1,2 ; Wang, Yu 3,4
	2024-08-22
发表期刊	CELL DEATH & DISEASE
ISSN	2041-4889
卷号	15 期号:8
发表状态	已发表
DOI	10.1038/s41419-024-07009-6
摘要	PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.
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收录类别	SCI
语种	英语
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:001296587900003
出版者	SPRINGERNATURE
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/415547
专题	生命科学与技术学院生命科学与技术学院_PI研究组_范高峰组生命科学与技术学院_PI研究组_王皞鹏组生命科学与技术学院_PI研究组_李磊组生命科学与技术学院_博士生
通讯作者	Fan, Gaofeng; Wang, Yu
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China 3.Tongji Univ, Shanghai Matern & Infant Hosp 1, Sch Med, Dept Gynecol, Shanghai 200092, Peoples R China 4.Tongji Univ, Shanghai Matern & Infant Hosp 1, Shanghai Inst Maternal Fetal Med & Gynecol Oncol, Clin & Translat Res Ctr,Shanghai Key Lab Maternal, Shanghai, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Huang, Mei,Zhu, Xiaotong,Wang, Chen,et al. PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells[J]. CELL DEATH & DISEASE,2024,15(8).
APA	Huang, Mei.,Zhu, Xiaotong.,Wang, Chen.,He, Liying.,Li, Lei.,...&Wang, Yu.(2024).PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells.CELL DEATH & DISEASE,15(8).
MLA	Huang, Mei,et al."PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells".CELL DEATH & DISEASE 15.8(2024).