1. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
2. Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

Correspondence to: Junjie Chen¹Zhenkun Lou² Correspondence and requests for materials should be addressed to J.C (Email: Junjie.Chen@yale.edu) or Z.L (Email: Lou.Zhenkun@mayo.edu).

Abstract

The NAD-dependent protein deacetylase Sir2 (silent information regulator 2) regulates lifespan in several organisms^{1, 2, 3}. SIRT1, the mammalian orthologue of yeast Sir2, participates in various cellular functions^{4, 5, 6, 7} and possibly tumorigenesis⁸. Whereas the cellular functions of SIRT1 have been extensively investigated, less is known about the regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1), initially cloned from a region (8p21) homozygously deleted in breast cancers⁹, forms a stable complex with SIRT1. DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo. Downregulation of DBC1 expression potentiates SIRT1-dependent inhibition of apoptosis induced by genotoxic stress. Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer.

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