title: Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.
abstract: The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis.
authors: Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors: Samuel T
authors: ST
authors: Fatoba
authors: Silvia
authors: S
authors: Tognetti
authors: Melissa
authors: M
authors: Berto
authors: Elisabetta
authors: E
authors: Leo
authors: Claire M
authors: CM
authors: Mulvey
authors: Jasminka
authors: J
authors: Godovac-Zimmermann
authors: Yves
authors: Y
authors: Pommier
authors: Andrei L
authors: AL
authors: Okorokov
mesh_terms: D000107:Acetylation; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication; D006801:Humans; D064110:Minichromosome Maintenance Proteins; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D018741:Replication Origin; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C489613:MCM10 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D064110:Minichromosome Maintenance Proteins