TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes

Gudjonsson, Thorkell, Altmeyer, Matthias, Savic, Velibor, Toledo, Luis, Dinant, Christoffel, Grøfte, Merete, Bartkova, Jirina, Poulsen, Maria, Oka, Yasuyoshi, Bekker-Jensen, Simon, Mailand, Niels, Neumann, Beate, Heriche, Jean-Karim, Shearer, Robert, Saunders, Darren, Bartek, Jiri, Lukas, Jiri and Lukas, Claudia (2012) TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell, 150 (4). pp. 697-709. ISSN 1097-4172

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Abstract

Histone ubiquitylation is a prominent response to DNA double-strand breaks (DSBs), but how these modifications are confined to DNA lesions is not understood. Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. Thus, regulatory and proteolytic ubiquitylations are wired in a self-limiting circuit that promotes histone ubiquitylation near the DNA lesions but at the same time counteracts its excessive spreading to undamaged chromosomes. We provide evidence that this mechanism is vital for the homeostasis of ubiquitin-controlled events after DNA breakage and can be subverted during tumorigenesis

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Q Science > QH Natural history > QH0301 Biology
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations
Depositing User: Velibor Savic
Date Deposited: 11 Feb 2013 14:04
Last Modified: 13 May 2015 12:53
URI: http://sro.sussex.ac.uk/id/eprint/43585
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