TY - JOUR
T1 - TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes
AU - Gudjónsson, Thorkell
AU - Altmeyer, Matthias Florian
AU - Savic, Velibor
AU - Toledo Lazaro, Luis Ignacio
AU - Dinant, Christoffel
AU - Grøfte, Merete
AU - Bartkova, Jirina
AU - Poulsen, Maria
AU - Oka, Yasuyoshi
AU - Bekker-Jensen, Simon
AU - Mailand, Niels
AU - Neumann, Beate
AU - Heriche, Jean-Karim
AU - Shearer, Robert
AU - Saunders, Darren
AU - Bartek, Jiri
AU - Lukas, Jiri
AU - Lukas, Claudia
N1 - Copyright © 2012 Elsevier Inc. All rights reserved.
PY - 2012/8/17
Y1 - 2012/8/17
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2012.06.039
DO - 10.1016/j.cell.2012.06.039
M3 - Journal article
C2 - 22884692
SN - 0092-8674
VL - 150
SP - 697
EP - 709
JO - Cell
JF - Cell
IS - 4
ER -