PARsylation-mediated ubiquitylation: lessons from rare hereditary disease Cherubism |
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Institution: | 1. Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada;2. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan;3. Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;4. Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada;5. Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada;6. Division of Rheumatology, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada |
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Abstract: | Modification of proteins by ADP-ribose (PARsylation) is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of enzymes exemplified by PARP1, which controls chromatin organization and DNA repair. Additionally, PARsylation induces ubiquitylation and proteasomal degradation of its substrates because PARsylation creates a recognition site for E3-ubiquitin ligase. The steady-state levels of the adaptor protein SH3-domain binding protein 2 (3BP2) is negatively regulated by tankyrase (PARP5), which coordinates ubiquitylation of 3BP2 by the E3-ligase ring finger protein 146 (RNF146). 3BP2 missense mutations uncouple 3BP2 from tankyrase-mediated negative regulation and cause Cherubism, an autosomal dominant autoinflammatory disorder associated with craniofacial dysmorphia. In this review, we summarize the diverse biological processes, including bone dynamics, metabolism, and Toll-like receptor (TLR) signaling controlled by tankyrase-mediated PARsylation of 3BP2, and highlight the therapeutic potential of this pathway. |
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