Histidine and tyrosine residues are targets for SIRT6 ADP-ribosylation activity
SIRT6, a highly conserved member of the sirtuin family, plays a critical role in diverse cellular processes, including gene regulation, DNA damage response and maintaining nuclear lamina integrity. These functions are essential in contexts such as differentiation, metabolic regulation, cancer development and ageing. Given the multifaceted influence of SIRT6 on cellular activities, there is an increasing interest in elucidating the regulatory mechanisms governing its enzymatic functions. SIRT6 exhibits two NAD+-dependent activities: deacetylation and ADP-ribosylation, with current research predominantly focusing on the former. However, the latter-its (ADP-ribosyl)transferase activity-remains underexplored, particularly concerning the specific amino acid targets it modifies and the (ADP-ribosyl)hydrolases that can reverse these modifications. In this study, we have utilized biochemical assays and proteomic techniques to investigate these aspects, revealing that SIRT6 transfers ADP-ribosyl moieties onto histidine and tyrosine residues. In addition, we reveal that the (ADP-ribosyl)hydrolase ARH3 has significant activity in erasing SIRT6-derived ADP-ribosylation in cells.
Authors
- Roberto Raggiaschi
- R. Lauro
- Gyula Timinszky (ORCID: https://orcid.org/0000-0001-6342-8985)
- Anna Georgina Kopasz (ORCID: https://orcid.org/0000-0002-8675-5185)
- Luca Palazzo (ORCID: https://orcid.org/0000-0002-5556-5549)
- Domagoj Baretić (ORCID: https://orcid.org/0000-0001-7049-3961)
- J.G.M. Rack (ORCID: https://orcid.org/0000-0001-8341-6439)
- Evgeniia Prokhorova (ORCID: https://orcid.org/0000-0002-5467-5586)
- Orsolya Leidecker (ORCID: https://orcid.org/0000-0001-5315-014X)
- Dmitri V. Filippov (ORCID: https://orcid.org/0000-0002-6978-7425)
- Ivan Ahel
- Jovana Mutabdzija
Institutions
- Leiden University (NL)
- University of Cologne (DE)
- University of Applied Sciences Leiden (NL)
- University of Szeged (HU)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- University of Oxford (GB)
- Federico II University Hospital (IT)
- Max Planck Institute for Biology of Ageing (DE)
- Health & Life (Taiwan) (TW)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Open Biology
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1098/rsob.250181
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Università degli Studi di Napoli Federico II
- Wellcome Trust
- Ovarian Cancer Research Alliance
- National Institute for Health and Care Research
- Department of Health and Social Care
- University of Exeter
- European Commission
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Magyarország Kormánya
- Medical Research Council Centre for Medical Mycology
- Directorate for Biological Sciences
- Medical Research Council