TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

Thorkell Gudjónsson; Matthias Florian Altmeyer; Velibor Savic; Luis Ignacio Toledo Lazaro; Christoffel Dinant; Merete Grøfte; Jirina Bartkova; Maria Poulsen; Yasuyoshi Oka; Simon Bekker-Jensen; Niels Mailand; Beate Neumann; Jean-Karim Heriche; Robert Shearer; Darren Saunders; Jiri Bartek; Jiri Lukas; Claudia Lukas

doi:10.1016/j.cell.2012.06.039

TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

Thorkell Gudjónsson, Matthias Florian Altmeyer, Velibor Savic, Luis Ignacio Toledo Lazaro, Christoffel Dinant, Merete Grøfte, Jirina Bartkova, Maria Poulsen, Yasuyoshi Oka, Simon Bekker-Jensen, Niels Mailand, Beate Neumann, Jean-Karim Heriche, Robert Shearer, Darren Saunders, Jiri Bartek, Jiri Lukas, Claudia Lukas

204 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	150
Udgave nummer	4
Sider (fra-til)	697-709
Antal sider	13
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2012.06.039
Status	Udgivet - 17 aug. 2012

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10.1016/j.cell.2012.06.039

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Gudjónsson, T., Altmeyer, M. F., Savic, V., Toledo Lazaro, L. I., Dinant, C., Grøfte, M., Bartkova, J., Poulsen, M., Oka, Y., Bekker-Jensen, S., Mailand, N., Neumann, B., Heriche, J.-K., Shearer, R., Saunders, D., Bartek, J., Lukas, J., & Lukas, C. (2012). TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes. Cell, 150(4), 697-709. https://doi.org/10.1016/j.cell.2012.06.039

Gudjónsson, T, Altmeyer, MF, Savic, V, Toledo Lazaro, LI, Dinant, C, Grøfte, M, Bartkova, J, Poulsen, M, Oka, Y, Bekker-Jensen, S , Mailand, N, Neumann, B, Heriche, J-K, Shearer, R, Saunders, D, Bartek, J, Lukas, J & Lukas, C 2012, 'TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes', Cell, bind 150, nr. 4, s. 697-709. https://doi.org/10.1016/j.cell.2012.06.039

@article{8f26c526245840848af650fde4975ff5,

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.",

author = "Thorkell Gudj{\'o}nsson and Altmeyer, {Matthias Florian} and Velibor Savic and {Toledo Lazaro}, {Luis Ignacio} and Christoffel Dinant and Merete Gr{\o}fte and Jirina Bartkova and Maria Poulsen and Yasuyoshi Oka and Simon Bekker-Jensen and Niels Mailand and Beate Neumann and Jean-Karim Heriche and Robert Shearer and Darren Saunders and Jiri Bartek and Jiri Lukas and Claudia Lukas",

year = "2012",

month = aug,

day = "17",

doi = "10.1016/j.cell.2012.06.039",

language = "English",

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journal = "Cell",

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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

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 -

TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

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