MCB Accepts, published online ahead of print on 15 October 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00504-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

UBE2T, the FA core complex and FANCD2 are recruited independently to chromatin: A basis for the regulation of FANCD2 monoubiquitination

Arno Alpi, Frederic Langevin, Georgina Mosedale, Yuichi J. Machida, Anindya Dutta, and Ketan J. Patel^*

Laboratory of Molecular Biology, Medical Research Council, Cambridge, UK; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia

^* To whom correspondence should be addressed. Email: kjp{at}mrc-lmb.cam.ac.uk.

The Fanconi anaemia (FA) nuclear core complex and the E2 ubiquitin conjugating enzyme UBE2T are required for the S phase and DNA damage restricted monoubiquitination of FANCD2. This constitutes a key step in the FA tumour suppressor pathway and much attention has been focused on the regulation at this point. Here, we address the importance of the assembly of the FA core complex and the subcellular localisation of UBE2T in the regulation of FANCD2 monoubiquitination. We establish three points. Firstly, the stable assembly of the FA core complex can be dissociated of its ability to function as an E3 ubiquitin ligase. Secondly, the actual E3 ligase activity is not determined by the assembly of the FA core complex, but rather by its DNA damage-induced localisation to chromatin. Finally, UBE2T and FANCD2 access this subcellular fraction independently of the FA core complex. FANCD2 monoubiquitination is therefore not regulated by multi protein complex assembly, but by the formation of an active E2/E3 holoenzyme on chromatin.

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