Toggle Main Menu Toggle Search

Open Access padlockePrints

Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres

Lookup NU author(s): Dr Vasileia Sapountzi, Professor David Lydall

Downloads


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. © 2008 European Molecular Biology Organization | All Rights Reserved.


Publication metadata

Author(s): Lazzaro F, Sapountzi V, Granata M, Pellicioli A, Vaze M, Haber JE, Plevani P, Lydall D, Muzi-Falconi M

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2008

Volume: 27

Issue: 10

Pages: 1502-1512

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/emboj.2008.81

DOI: 10.1038/emboj.2008.81

PubMed id: 18418382


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
075294Wellcome Trust
C23629/A7951Cancer Research UK
GGP030406Telethon
GM20056NIGMS NIH HHS
GM61766NIGMS NIH HHS
R01 GM020056NIGMS NIH HHS
R01 GM061766-07NIGMS NIH HHS
R37 GM020056NIGMS NIH HHS
R01 GM020056-33NIGMS NIH HHS
R01 GM061766NIGMS NIH HHS
R01 GM061766-06NIGMS NIH HHS

Share