Abstract
BRCA1 associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates tumor suppressor activity and widely involves many cellular processes ranging from cell cycle regulation to gluconeogenesis. Impairment of enzymatic activity and nuclear localization induce abnormal cell proliferation. It is considered to be an important driver gene, which undergoes frequent mutations in several cancers. However the role of mutation and oncogenic gain of function of BAP1 are poorly understood. Here, we investigated cellular localization, enzymatic activity and structural changes for four missense mutants of the catalytic domain of BAP1, which are prevalent in different types of cancer. These mutations triggered cytoplasmic/perinuclear accumulation in BAP1 deficient cells, which has been observed in proteins that undergo aggregation in cellular condition. Amyloidogenic activity of mutant BAP1 was revealed from its reactivity towards anti oligomeric antibody in HEK293T cells. We have also noted structural destabilization in the catalytic domain mutants, which eventually produced beta amyloid structure as indicated in atomic force microscopy study. The cancer associated mutants up-regulate heat shock response and activates transcription of genes normally co-repressed by BAP1. Overall, our results unambiguously demonstrate that structural destabilization and subsequent aggregation abrogate its cellular mechanism leading to adverse outcome.
Highlights
Human BRCA1 associated protein 1 (BAP1) is deubiquitinating enzyme consisting of 729 amino acid whose N-terminal catalytic domain (1–240) shows homology to other ubiquitin C-terminal hydrolase (UCH) enzymes[6]
Previous reports of BAP1 mutations showed wide range of consequences on tumor suppressor activity that contributes to oncogenic progression[4,5]
Different types of mutations are found but missense type is predominant in UCH domain which is the core activity domain of BAP11,57
Summary
Human BAP1 is deubiquitinating enzyme consisting of 729 amino acid whose N-terminal catalytic domain (1–240) shows homology to other ubiquitin C-terminal hydrolase (UCH) enzymes[6]. While BAP1 and its involvement in cancer is typically caused by mutations that lead to loss of protein function or deletion of key regulatory domains, missense mutations are more prevalent in tumors[1,25]. Small molecules are identified to stabilize the aggregating mutants of p53 which might play a role in improvement of cancer[44,47] It remains unexplored how protein aggregation caused by alteration of protein structure oncogene or tumor suppressor leads to induction of malignancy. To address these questions, we have screened missense mutations in genomic landscape of BAP1 and found that catalytic domain mutations play an important role in oncogenic progression. Our results indicate loss of BAP1 function due to aggregation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
