title: TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes.
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.
authors.affiliation: Chromosome Biology Unit, Danish Cancer Society Research Center and Center for Genotoxic Stress Research, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Thorkell
authors.initials: T
authors.lastname: Gudjonsson
authors.forename: Matthias
authors.initials: M
authors.lastname: Altmeyer
authors.forename: Velibor
authors.initials: V
authors.lastname: Savic
authors.forename: Luis
authors.initials: L
authors.lastname: Toledo
authors.forename: Christoffel
authors.initials: C
authors.lastname: Dinant
authors.forename: Merete
authors.initials: M
authors.lastname: Grøfte
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Maria
authors.initials: M
authors.lastname: Poulsen
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Oka
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
authors.forename: Beate
authors.initials: B
authors.lastname: Neumann
authors.forename: Jean-Karim
authors.initials: JK
authors.lastname: Heriche
authors.forename: Robert
authors.initials: R
authors.lastname: Shearer
authors.forename: Darren
authors.initials: D
authors.lastname: Saunders
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
mesh_terms: D052685:Alphapapillomavirus; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C530813:TRIP12 protein, human; C117617:UBR5 protein, human; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases