Fatoba, ST;
Tognetti, S;
Berto, M;
Leo, E;
Mulvey, CM;
Godovac-Zimmermann, J;
Pommier, Y;
(2013)
Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.
Nucleic Acids Research
, 41
(7)
4065 - 4079.
10.1093/nar/gkt131.
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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.
| Type: | Article |
|---|---|
| Title: | Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/nar/gkt131 |
| Publisher version: | http://dx.doi.org/10.1093/nar/gkt131 |
| Language: | English |
| Additional information: | © The Author(s) 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3627603 |
| Keywords: | Acetylation, Cell Cycle, Cell Cycle Proteins, Cell Line, Chromatin, DNA Replication, Humans, Protein Binding, Protein Interaction Domains and Motifs, Protein Stability, Replication Origin, Sirtuin 1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1386049 |
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