Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

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Journal
Science Translational Medicine
Published
2026-04-01
DOI
https://doi.org/10.1126/scitranslmed.adr6668
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
0.00

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article

Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

Amrita M. Nargund, Abner Herbert Lim, Cedric Chuan Young Ng, Takeshi Hagihara et al.
Science Translational Medicine
PARP inhibition in cancer therapy
article

Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers

Amrita M. Nargund, Abner Herbert Lim, Cedric Chuan Young Ng, Takeshi Hagihara, Sudhakar Jha, Pek Lim Chu, Kah Suan Lim, Chern Han Yong, Sheng Rong Ng, Bin Tean Teh, Z. Li, Radoslaw M. Sobota, Nhu‐An Pham, James Brugarolas, Jabed Iqbal, Peiyong Guan, Sarinya Kongpetch, Loo Chien Wang, Xiaosai Yao, Shang Li, Clara Shi Ya Ng, Jing Yi Lee, Bin Sing Teh, David Wai Meng Tai, Patrick Tan, Xiu Yi Kwek, R Xiao, Hong Lee Heng, Apinya Jusakul, Masahiro Sugiura, Peili Wang, Poramate Klanrit, Wei Liu, Zihao Lin, Jianfeng Chen, Watcharin Loilome, Jing Tan, Jason Yongsheng Chan
article en

Abstract

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

Science Translational MedicineVol. 18(843)
Agency for Science, Technology and Research (SG), Oklahoma State University (US), Memorial Sloan Kettering Cancer Center (US), Sun Yat-sen University (CN), National University of Singapore (SG), Khon Kaen University (TH), Singapore General Hospital (SG), Princess Margaret Cancer Centre (CA), Third Affiliated Hospital of Guangzhou Medical University (CN), National University Cancer Institute, Singapore (SG), Methodist Hospital (US), KK Women's and Children's Hospital (SG), Guangzhou First People's Hospital (CN), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), Sun Yat-sen University Cancer Center (CN), Genome Institute of Singapore (SG), Institute of Molecular and Cell Biology (SG), Hainan Medical University (CN), The University of Texas Southwestern Medical Center (US), Guangzhou Medical University (CN)
National Natural Science Foundation of China
Openalex Percentile: Top 42%
PARP inhibition in cancer therapy
DOISourceOpenAlex
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