Title |
The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by Regulating CLASPIN during S-Phase
|
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Published in |
Cancer Research, April 2016
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DOI | 10.1158/0008-5472.can-15-2890 |
Pubmed ID | |
Authors |
Edel McGarry, David Gaboriau, Michael D. Rainey, Umberto Restuccia, Angela Bachi, Corrado Santocanale |
Abstract |
Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in replication fork stabilization and checkpoint responses, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, we used a quantitative proteomics approach and identified USP9X as a novel CLASPIN interacting protein. USP9X is a deubiquitinase involved in multiple signaling and survival pathways whose tumor suppressor or oncogenic activity is highly context-dependent. We found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage. Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of DNA damage. Furthermore, USP9X depletion compromised CHK1 activation in response to hydroxyurea and UV, thus promoting hypersensitivity to drug-induced replication stress. Taken together, our results reveal a novel role for USP9X in the maintenance of genomic stability during DNA replication, and provide potential mechanistic insights into its tumor suppressor role in certain malignancies. |
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Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 10 | 14% |
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Unspecified | 1 | 1% |
Other | 2 | 3% |
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