Article
- The EMBO Journal (2008) 27, 1502 - 1512
- doi:10.1038/emboj.2008.81
Published online: 17 April 2008
Subject Category:
Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeresEMBO Open
Federico Lazzaro1,a, Vasileia Sapountzi2,a, Magda Granata1, Achille Pellicioli1, Moreshwar Vaze3,b, James E Haber3, Paolo Plevani1, David Lydall2 and Marco Muzi-Falconi1
- Dipartimento di Scienze Biomolecolari e Biotecnologie, Universita' degli Studi di Milano, Milano, Italy
- Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Henry Wellcome Laboratory for Biogerontology Research, Newcastle University, Newcastle upon Tyne, UK
- Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA
Correspondence to:
Paolo PlevaniMarco Muzi-Falconi, Dipartimento di Scienze Biomolecolari e Biotecnologie, Universita' degli Studi di Milano, Via Celoria 26, Milano 20133, Italy. Tel.: +39 02 50315034; Fax: +39 02 50315044; E-mail: marco.muzifalconi@unimi.it
David Lydall, Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Henry Wellcome Laboratory for Biogerontology Research, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Tel.: +44 191 256 3449; Fax: +44 191 256 3445; E-mail: d.a.lydall@ncl.ac.uk
aThese authors contributed equally to this work
bPresent address: Boston Biomedicals Inc., Norwood, MA 0206, USA
Received 2 February 2008; Accepted 26 March 2008
Abstract
Cells respond to DNA double-strand breaks (DSBs) and uncapped telomeres by recruiting checkpoint and repair factors to the site of lesions. Single-stranded DNA (ssDNA) is an important intermediate in the repair of DSBs and is produced also at uncapped telomeres. Here, we provide evidence that binding of the checkpoint protein Rad9, through its Tudor domain, to methylated histone H3-K79 inhibits resection at DSBs and uncapped telomeres. Loss of DOT1 or mutations in RAD9 influence a Rad50-dependent nuclease, leading to more rapid accumulation of ssDNA, and faster activation of the critical checkpoint kinase, Mec1. Moreover, deletion of RAD9 or DOT1 partially bypasses the requirement for CDK1 in DSB resection. Interestingly, Dot1 contributes to checkpoint activation in response to low levels of telomere uncapping but is not essential with high levels of uncapping. We suggest that both Rad9 and histone H3 methylation allow transmission of the damage signal to checkpoint kinases, and keep resection of damaged DNA under control influencing, both positively and negatively, checkpoint cascades and contributing to a tightly controlled response to DNA damage.
Keywords:
- chromatin,
- DNA damage checkpoint,
- DNA repair,
- histone methylation,
- telomeres
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.
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