RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

Carsten Doil; Niels Mailand; Simon Bekker-Jensen; Patrice Menard; Dorthe Helena Larsen; Rainer Pepperkok; Jan Ellenberg; Stephanie Panier; Daniel Durocher; Jiri Bartek; Jiri Lukas; Claudia Lukas

doi:10.1016/j.cell.2008.12.041

RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

Carsten Doil, Niels Mailand, Simon Bekker-Jensen, Patrice Menard, Dorthe Helena Larsen, Rainer Pepperkok, Jan Ellenberg, Stephanie Panier, Daniel Durocher, Jiri Bartek, Jiri Lukas, Claudia Lukas

629 Citations (Scopus)

Abstract

DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.

Original language	English
Journal	Cell
Volume	136
Issue number	3
Pages (from-to)	435-46
Number of pages	11
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2008.12.041
Publication status	Published - 2009
Externally published	Yes

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@article{2a7e8e90333311df8ed1000ea68e967b,

title = "RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins",

abstract = "DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.",

author = "Carsten Doil and Niels Mailand and Simon Bekker-Jensen and Patrice Menard and Larsen, {Dorthe Helena} and Rainer Pepperkok and Jan Ellenberg and Stephanie Panier and Daniel Durocher and Jiri Bartek and Jiri Lukas and Claudia Lukas",

note = "Keywords: Cell Line; Chromosomes; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins; Gene Knockdown Techniques; Histones; Humans; Intracellular Signaling Peptides and Proteins; Protein Structure, Tertiary; Ubiquitin; Ubiquitin-Protein Ligases",

year = "2009",

doi = "10.1016/j.cell.2008.12.041",

language = "English",

volume = "136",

pages = "435--46",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

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TY - JOUR

T1 - RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

AU - Doil, Carsten

AU - Mailand, Niels

AU - Bekker-Jensen, Simon

AU - Menard, Patrice

AU - Larsen, Dorthe Helena

AU - Pepperkok, Rainer

AU - Ellenberg, Jan

AU - Panier, Stephanie

AU - Durocher, Daniel

AU - Bartek, Jiri

AU - Lukas, Jiri

AU - Lukas, Claudia

N1 - Keywords: Cell Line; Chromosomes; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins; Gene Knockdown Techniques; Histones; Humans; Intracellular Signaling Peptides and Proteins; Protein Structure, Tertiary; Ubiquitin; Ubiquitin-Protein Ligases

PY - 2009

Y1 - 2009

N2 - DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.

AB - DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.

U2 - 10.1016/j.cell.2008.12.041

DO - 10.1016/j.cell.2008.12.041

M3 - Journal article

C2 - 19203579

SN - 0092-8674

VL - 136

SP - 435

EP - 446

JO - Cell

JF - Cell

IS - 3

ER -

RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

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