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. Copyright 2012 Elsevier Inc. All rights reserved.
- MeSH
- Alphapapillomavirus MeSH
- buněčné linie MeSH
- chromatin * metabolismus MeSH
- dvouřetězcové zlomy DNA * MeSH
- genetická transkripce MeSH
- infekce papilomavirem metabolismus patologie MeSH
- intracelulární signální peptidy a proteiny metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory metabolismus patologie virologie MeSH
- oprava DNA * MeSH
- transportní proteiny * metabolismus MeSH
- ubikvitinace MeSH
- ubikvitinligasy * metabolismus MeSH
- umlčování genů MeSH
- Check Tag
- lidé MeSH
