Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks
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Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks. / Poulsen, Maria; Lukas, Claudia; Lukas, Jiri; Bekker-Jensen, Simon; Mailand, Niels.
In: Journal of Cell Biology, Vol. 197, No. 2, 2012, p. 189-99.Research output: Contribution to journal › Journal article › peer-review
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T1 - Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks
AU - Poulsen, Maria
AU - Lukas, Claudia
AU - Lukas, Jiri
AU - Bekker-Jensen, Simon
AU - Mailand, Niels
PY - 2012
Y1 - 2012
N2 - Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80-BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization.
AB - Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80-BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization.
KW - BRCA1 Protein
KW - Carrier Proteins
KW - Cell Line, Tumor
KW - Cell Survival
KW - Chromatin
KW - DNA
KW - DNA Breaks, Double-Stranded
KW - DNA End-Joining Repair
KW - DNA-Binding Proteins
KW - HEK293 Cells
KW - HeLa Cells
KW - Homologous Recombination
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Nuclear Proteins
KW - RNA Interference
KW - RNA, Small Interfering
KW - Ubiquitin
KW - Ubiquitin-Protein Ligases
KW - Ubiquitination
KW - Zinc Fingers
U2 - 10.1083/jcb.201109100
DO - 10.1083/jcb.201109100
M3 - Journal article
C2 - 22492721
VL - 197
SP - 189
EP - 199
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 2
ER -
ID: 40289827