About: TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	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 supra-physiological 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. 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 supra-physiological 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. (en)
Title	TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes (en)
skos:prefLabel	TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes (en)
skos:notation	RIV/61989592:15110/12:33140876!RIV13-MSM-15110___
http://linked.open...avai/predkladatel	Lékařská fakulta
http://linked.open...avai/riv/aktivita	P
http://linked.open...avai/riv/aktivity	P(ED0030/01/01)
http://linked.open...iv/cisloPeriodika	4
http://linked.open...vai/riv/dodaniDat	2013
http://linked.open...aciTvurceVysledku	Bártek, Jiří
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Palackého v Olomouci / Lékařská fakulta
http://linked.open...dnocenehoVysledku	175209
http://linked.open...ai/riv/idVysledku	RIV/61989592:15110/12:33140876
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	REPAIR PROTEINS; BRCA1 DEFICIENCY; REPLICATION STRESS; GENOMIC INSTABILITY; HOMOLOGOUS RECOMBINATION; DNA-DAMAGE; END RULE PATHWAY; CLASS SWITCH RECOMBINATION; E3 UBIQUITIN LIGASE; DOUBLE-STRAND BREAKS (en)
http://linked.open.../riv/klicoveSlovo	BRCA1 DEFICIENCY E3 UBIQUITIN LIGASE END RULE PATHWAY REPAIR PROTEINS CLASS SWITCH RECOMBINATION REPLICATION STRESS GENOMIC INSTABILITY HOMOLOGOUS RECOMBINATION DOUBLE-STRAND BREAKS DNA-DAMAGE
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[4634AE72C125]
http://linked.open...i/riv/nazevZdroje	Cell
http://linked.open...in/vavai/riv/obor	FD
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	18 (xsd:int)
http://linked.open...vavai/riv/projekt	Biomedicine for regional development and human resources
http://linked.open...UplatneniVysledku	2012
http://linked.open...v/svazekPeriodika	150
http://linked.open...iv/tvurceVysledku	Bártek, Jiří Bartkova, J. Lukas, J. Lukas, C. Neumann, B. Altmeyer, M. Bekker-Jensen, S. Dinant, Ch. Grofte, M. Gudjonsson, T. Heriche, Jk Mailand, N. Oka, Y. Poulsen, M. Saunders, D. Savic, V. Shearer, R. Toledo, L.
http://linked.open...ain/vavai/riv/wos	000308002300006
issn	0092-8674
number of pages	13 (xsd:int)
http://bibframe.org/vocab/doi	10.1016/j.cell.2012.06.039
http://localhost/t...ganizacniJednotka	15110
is http://linked.open...avai/riv/vysledek of	TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

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