TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes

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 pathw...

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Vydáno v:Cell Ročník 150; číslo 4; s. 697
Hlavní autoři: 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, Lukas, Claudia
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 17.08.2012
Témata:
Alphapapillomavirus
Carrier Proteins - metabolism
Cell Line
Cell Line, Tumor
Chromatin - metabolism
DNA Breaks, Double-Stranded
DNA Repair
Gene Silencing
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Neoplasms - metabolism
Neoplasms - pathology
Neoplasms - virology
Papillomavirus Infections - metabolism
Papillomavirus Infections - pathology
Transcription, Genetic
Tumor Suppressor p53-Binding Protein 1
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
ISSN:1097-4172, 1097-4172
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2012.06.039