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
VL - 136
SP - 435
EP - 446
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -