TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes

被引：280

作者：

Gudjonsson, Thorkell ^{[1
]}

Altmeyer, Matthias ^{[1
]}

Savic, Velibor ^{[1
]}

Toledo, Luis ^{[1
]}

Dinant, Christoffel ^{[2
,3
]}

Grofte, Merete ^{[1
]}

Bartkova, Jirina ^{[2
,3
]}

Poulsen, Maria ^{[4
]}

Oka, Yasuyoshi ^{[4
]}

Bekker-Jensen, Simon ^{[4
]}

Mailand, Niels ^{[4
]}

Neumann, Beate ^{[5
]}

Heriche, Jean-Karim ^{[5
]}

Shearer, Robert ^{[6
,7
]}

Saunders, Darren ^{[6
,7
]}

Bartek, Jiri ^{[2
,3
,8
]}

Lukas, Jiri ^{[1
,4
]}

Lukas, Claudia ^{[1
]}

机构：

[1] Danish Canc Soc Res Ctr, Chromosome Biol Unit, DK-2100 Copenhagen, Denmark

[2] Danish Canc Soc Res Ctr, Genome Integr Unit, DK-2100 Copenhagen, Denmark

[3] Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark

[4] Univ Copenhagen, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark

[5] European Mol Biol Lab, D-69117 Heidelberg, Germany

[6] Univ New S Wales, Canc Res Program, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia

[7] Univ New S Wales, St Vincents Clin Sch, Fac Med, Darlinghurst, NSW 2010, Australia

[8] Palacky Univ, Fac Med, Inst Mol & Translat Med, CZ-77515 Olomouc, Czech Republic

来源：

CELL | 2012年 / 150卷 / 04期

基金：

新加坡国家研究基金会;

关键词：

E3 UBIQUITIN LIGASE; DOUBLE-STRAND BREAKS; END RULE PATHWAY; DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; S-PHASE; 53BP1; REPAIR; EDD;

D O I：

10.1016/j.cell.2012.06.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：697 / 709

页数：13

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