Uncovering BAP1 deubiquitination landscape enhances mechanism elucidation and therapeutic precision for BAP1-deficient pancancers - PubMed
4 hours ago
- #BAP1
- #Synthetic Lethality
- #Nucleotide Excision Repair
- BAP1 mutations occur in aggressive cancers like cholangiocarcinoma and mesothelioma, but comprehensive pancancer studies are scarce.
- A pancancer approach using ubiquitin remnant pulldown and mass spectrometry maps proteins deubiquitinated by BAP1.
- BAP1 enhances global genome nucleotide excision repair (GG-NER) by deubiquitinating DDB1, RAD23B, and COPS7B.
- High-throughput screening identifies LSD1 and PARP1 as synthetic lethal partners of BAP1.
- BAP1, LSD1, and PARP1 colocalize on chromatin, with LSD1 aiding chromatin relaxation for transcription-coupled NER (TC-NER).
- Combined inhibition of LSD1 and PARP1 synergistically blocks NER, induces apoptosis, and reduces tumor growth in BAP1-deficient cancer models.
- The study offers a BAP1 deubiquitination landscape, mechanistic insights, and a potential therapy for BAP1-deficient pancancers.