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Ataxin‐3 consolidates the MDC 1‐dependent DNA double‐strand break response by counteracting the SUMO ‐targeted ubiquitin ligase RNF 4
Author(s) -
Pfeiffer Annika,
Luijsterburg Martijn S,
Acs Klara,
Wiegant Wouter W,
Helfricht Angela,
Herzog Laura K,
Minoia Melania,
Böttcher Claudia,
Salomons Florian A,
Attikum Haico,
Dantuma Nico P
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695151
Subject(s) - ubiquitin ligase , homologous recombination , dna ligase , ubiquitin , microbiology and biotechnology , biology , dna damage , dna repair , dna , biochemistry , gene
The SUMO ‐targeted ubiquitin ligase RNF 4 functions at the crossroads of the SUMO and ubiquitin systems. Here, we report that the deubiquitylation enzyme ( DUB ) ataxin‐3 counteracts RNF 4 activity during the DNA double‐strand break ( DSB ) response. We find that ataxin‐3 negatively regulates ubiquitylation of the checkpoint mediator MDC 1, a known RNF 4 substrate. Loss of ataxin‐3 markedly decreases the chromatin dwell time of MDC 1 at DSB s, which can be fully reversed by co‐depletion of RNF 4. Ataxin‐3 is recruited to DSB s in a SUMO ylation‐dependent fashion, and in vitro it directly interacts with and is stimulated by recombinant SUMO , defining a SUMO ‐dependent mechanism for DUB activity toward MDC 1. Loss of ataxin‐3 results in reduced DNA damage‐induced ubiquitylation due to impaired MDC 1‐dependent recruitment of the ubiquitin ligases RNF 8 and RNF 168, and reduced recruitment of 53 BP 1 and BRCA 1. Finally, ataxin‐3 is required for efficient MDC 1‐dependent DSB repair by non‐homologous end‐joining and homologous recombination. Consequently, loss of ataxin‐3 sensitizes cells to ionizing radiation and poly( ADP ‐ribose) polymerase inhibitor. We propose that the opposing activities of RNF 4 and ataxin‐3 consolidate robust MDC 1‐dependent signaling and repair of DSB s.