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| PCNA monoubiquitination: USP1 regulates Translesion DNA synthesis
The deubiquitinating enzyme USP1 autocleaves upon UV irradiation, causing the accumulation of monoubiquitinated PCNA and the subsequent localization of Polη to DNA repair foci. The opposing activities of ubiquitin E3 ligases and deubiquitinating enzymes (DUBs) regulate the reversible ubiquitination of proteins. Alan D’Andrea and colleagues now show in Nature Cell Biology that the DUB ubiquitin specific protease 1 (USP1) deubiquitinates the DNA replication processivity factor PCNA. Cellular stress, such as UV irradiation, causes USP1 auto-cleavage, allowing monoubiquitinated PCNA to accumulate and translesion synthesis (TLS) of UV damaged DNA to commence.
DUBs are cysteine proteases that cleave mono- and poly-ubiquitinated substrates. USP1 was previously shown to be a negative regulator of the Fanconi anemia pathway through the deubiquitination of the Fanconi anemia effector protein D2 (FANCD2). As PCNA co-localizes with FANCD2 at the DNA replication fork after UV damage, the authors hypothesized that USP1 may also target monoubiquitinated PCNA. siRNA-mediated knockdown of USP1 causes elevated levels of monoubiquitinated PCNA. The authors show for the first time that USP1 undergoes proteolysis in UV treated cells, leading to an accumulation of monoubiquitinated PCNA. Furthermore, USP1 specifically deubiquitinates recombinant PCNA, while an unrelated DUB does not. Mass spectrometric analysis was employed to map the USP1 cleavage. Mutation of two residues proximal to the USP1 cleavage site ablates USP1’s ability to auto-cleave without affecting its DUB activity. It is known that monoubiquitinated PCNA facilitates the localization of the translesion DNA polymerase pol This study reveals how UV irradiation triggers the cleavage of USP1, thereby inhibiting PCNA deubiquitination. Whether other DUBs are also autoregulated has yet to be determined. Clare Garvey
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to DNA repair foci. The authors show that stabilized USP1 point mutants inhibit PCNA monoubiquitination, resulting in a reduction in the formation of pol