RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. / Mailand, Niels; Bekker-Jensen, Simon; Faustrup, Helene; Melander, Fredrik; Bartek, Jiri; Lukas, Claudia; Lukas, Jiri.
I: Cell, Bind 131, Nr. 5, 2007, s. 887-900.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins
AU - Mailand, Niels
AU - Bekker-Jensen, Simon
AU - Faustrup, Helene
AU - Melander, Fredrik
AU - Bartek, Jiri
AU - Lukas, Claudia
AU - Lukas, Jiri
PY - 2007
Y1 - 2007
N2 - Accumulation of repair proteins on damaged chromosomes is required to restore genomic integrity. However, the mechanisms of protein retention at the most destructive chromosomal lesions, the DNA double-strand breaks (DSBs), are poorly understood. We show that RNF8, a RING-finger ubiquitin ligase, rapidly assembles at DSBs via interaction of its FHA domain with the phosphorylated adaptor protein MDC1. This is accompanied by an increase in DSB-associated ubiquitylations and followed by accumulation of 53BP1 and BRCA1 repair proteins. Knockdown of RNF8 or disruption of its FHA or RING domains impaired DSB-associated ubiquitylation and inhibited retention of 53BP1 and BRCA1 at the DSB sites. In addition, we show that RNF8 can ubiquitylate histone H2A and H2AX, and that its depletion sensitizes cells to ionizing radiation. These data suggest that MDC1-mediated and RNF8-executed histone ubiquitylation protects genome integrity by licensing the DSB-flanking chromatin to concentrate repair factors near the DNA lesions.
AB - Accumulation of repair proteins on damaged chromosomes is required to restore genomic integrity. However, the mechanisms of protein retention at the most destructive chromosomal lesions, the DNA double-strand breaks (DSBs), are poorly understood. We show that RNF8, a RING-finger ubiquitin ligase, rapidly assembles at DSBs via interaction of its FHA domain with the phosphorylated adaptor protein MDC1. This is accompanied by an increase in DSB-associated ubiquitylations and followed by accumulation of 53BP1 and BRCA1 repair proteins. Knockdown of RNF8 or disruption of its FHA or RING domains impaired DSB-associated ubiquitylation and inhibited retention of 53BP1 and BRCA1 at the DSB sites. In addition, we show that RNF8 can ubiquitylate histone H2A and H2AX, and that its depletion sensitizes cells to ionizing radiation. These data suggest that MDC1-mediated and RNF8-executed histone ubiquitylation protects genome integrity by licensing the DSB-flanking chromatin to concentrate repair factors near the DNA lesions.
KW - BRCA1 Protein
KW - Binding Sites
KW - Cell Survival
KW - Chromatin
KW - DNA Breaks, Double-Stranded
KW - DNA Repair Enzymes
KW - DNA-Binding Proteins
KW - Histones
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Models, Biological
KW - Nuclear Proteins
KW - Phosphorylation
KW - Protein Binding
KW - Protein Structure, Tertiary
KW - Trans-Activators
KW - Tumor Cells, Cultured
KW - Ubiquitination
U2 - 10.1016/j.cell.2007.09.040
DO - 10.1016/j.cell.2007.09.040
M3 - Journal article
C2 - 18001824
VL - 131
SP - 887
EP - 900
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -
ID: 40291232