Human Molecular Genetics Advance Access originally published online on August 4, 2009
Human Molecular Genetics 2009 18(21):4180-4188; doi:10.1093/hmg/ddp370
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A conserved role for the mitochondrial citrate transporter Sea/SLC25A1 in the maintenance of chromosome integrity
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1 Dipartimento di Biologia di Base ed Applicata, Università dell'Aquila, 67010 L'Aquila, Italy 2 Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali 3 Dipartimento dei Beni Artistici e Storici, Università del Salento, 73100 Lecce, Italy 4 Istituto di Tecnologie Biomediche, CNR, 56124 Pisa, Italy 5 Dipartimento di Biologia Cellulare e dello Sviluppo and Istituto Telethon Dulbecco, Universita’ degli Studi di Palermo, 90127 Palermo, Italy 6 Dipartimento di Genetica e Biologia Molecolare, Università La Sapienza, 00185 Roma, Italy 7 Istituto Toscano Tumori, 50139 Firenze, Italy
* To whom correspondence should be addressed at: Dipartimento di Biologia di Base ed Applicata, Università dell'Aquila, Via Vetoio, Loc. Coppito, 67010 Coppito, L'Aquila, Italy. Tel: +39 0862433299/+39 0862433553; Fax: +39 0862433273; Email: giovanni.cenci{at}cc.univaq.it
Received June 17, 2009; Accepted July 31, 2009
Histone acetylation plays essential roles in cell cycle progression, DNA repair, gene expression and silencing. Although the knowledge regarding the roles of acetylation of histone lysine residues is rapidly growing, very little is known about the biochemical pathways providing the nucleus with metabolites necessary for physiological chromatin acetylation. Here, we show that mutations in the scheggia (sea)-encoded Sea protein, the Drosophila ortholog of the human mitochondrial citrate carrier Solute carrier 25 A1 (SLC25A1), impair citrate transport from mitochondria to the cytosol. Interestingly, inhibition of sea expression results in extensive chromosome breakage in mitotic cells and induces an ATR-dependent cell cycle arrest associated with a dramatic reduction of global histone acetylation. Notably, loss of SLC25A1 in short interfering RNA (siRNA)-treated human primary fibroblasts also leads to chromosome breaks and histone acetylation defects, suggesting an evolutionary conserved role for Sea/SLC25A1 in the regulation of chromosome integrity. This study therefore provides an intriguing and unexpected link between intermediary metabolism and epigenetic control of genome stability.
Present address: LBMB, NCI, NIH, Bethesda, MD 20892, USA.
These authors contributed equally to this work.
This article is dedicated to the memory of our University of L'Aquila students Nicola Bianchi and Giusy Antonini whose dreams of being scientists were dramatically shattered by the 6th April ‘09 earthquake.