Sirtuin 1 (SIRT1)–Cell division cycle and apoptosis regulator protein 2 (DBC1) protein–protein interaction (SIRT1–DBC1 PPI)

The Sirtuin 1 (SIRT1)–Cell division cycle and apoptosis regulator protein 2 (DBC1) protein–protein interaction is a fundamental regulatory mechanism for SIRT1, an NAD+-dependent deacetylase that governs aging, metabolism, and stress responses [1, 5]. DBC1, also known as Deleted in Breast Cancer 1, serves as a potent endogenous inhibitor by binding to the catalytic domain of SIRT1 and physically blocking its access to substrates [2, 7]. This interaction prevents the deacetylation of key proteins such as the tumor suppressor p53 and the metabolic regulator PGC-1α, thereby modulating apoptosis and energy homeostasis [3, 4]. In many cancers, the SIRT1–DBC1 complex is dysregulated, often leading to the suppression of p53-mediated cell death and promoting tumor survival [6, 9]. Conversely, in metabolic diseases like obesity and type 2 diabetes, the interaction remains overly stable, contributing to reduced SIRT1 activity and impaired mitochondrial function [8, 11]. Pharmacological strategies aim to disrupt this protein-protein interaction to restore or enhance SIRT1 activity, offering a therapeutic avenue for metabolic and age-related diseases [2, 12]. While some SIRT1 inhibitors like EX-527 can block this interaction, the development of specific disruptors that activate SIRT1 by preventing DBC1 binding is an active area of drug discovery [2, 13]. This target represents a novel approach to treating age-related pathologies by harnessing the body's endogenous regulatory pathways [1, 8].

Other names

SIRT1–DBC1 interactionSIRT1–CCAR2 interactionSirtuin 1–Deleted in Breast Cancer 1 interactionSIRT1–KIAA1967 interaction

Small molecules or post-translational modifications disrupt the physical binding between the DBC1 S1-like domain and the SIRT1 catalytic or N-terminal region, thereby relieving endogenous inhibition and restoring SIRT1 deacetylase activity.