University of Sussex
Browse

File(s) not publicly available

TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes

journal contribution
posted on 2023-06-08, 14:17 authored by Thorkell Gudjonsson, Matthias Altmeyer, Velibor Savic, Luis Toledo, Christoffel Dinant, Merete Grøfte, Jirina Bartkova, Maria Poulsen, Yasuyoshi Oka, Simon Bekker-Jensen, Niels Mailand, Beate Neumann, Jean-Karim Heriche, Robert Shearer, Darren Saunders, Jiri Bartek, Jiri Lukas, Claudia Lukas
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

History

Publication status

  • Published

Journal

Cell

ISSN

1097-4172

Publisher

Elsevier

Issue

4

Volume

150

Page range

697-709

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2013-02-11

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC