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Published December 28, 2012 | Accepted Version
Journal Article Open

The Auto-Generated Fragment of the Usp1 Deubiquitylase Is a Physiological Substrate of the N-End Rule Pathway


Deamidation of N-terminal Gln by the Ntaq1 Nt^Q-amidase is a part of the Arg/N-end rule pathway, a ubiquitin-dependent proteolytic system. Here we identify Gln-Usp1^(Ct), the C-terminal fragment of the autocleaved Usp1 deubiquitylase, as the first physiological Arg/N-end rule substrate that is targeted for degradation through deamidation of N-terminal Gln. Usp1 regulates genomic stability, in part through the deubiquitylation of monoubiquitylated PCNA, a DNA polymerase processivity factor. The autocleaved Usp1 remains a deubiquitylase because its fragments remain associated with Uaf1, an enhancer of Usp1 activity, until the Gln-Usp1^(Ct) fragment is selectively destroyed by the Arg/N-end rule pathway. We also show that metabolic stabilization of Gln-Usp1^(Ct) results in a decreased monoubiquitylation of PCNA and in a hypersensitivity of cells to ultraviolet irradiation. Thus, in addition to its other functions in DNA repair and chromosome segregation, the Arg/N-end rule pathway regulates genomic stability through the degradation-mediated control of the autocleaved Usp1 deubiquitylase.

Additional Information

© 2012 Elsevier Inc. Received: July 16, 2012; Revised: September 21, 2012; Accepted: October 2, 2012; Published online: November 15, 2012. We are grateful to A. D'Andrea for the anti-USP1Cterm antibody. We thank members of the Varshavsky, Huang, Bar-Sagi, and Reinberg laboratories for their reagents, advice, assistance, and equipment. This study was supported by NIH grants to A.V. (DK039520 and GM031530) and T.H. (GM084244) and by an American Cancer Society grant to T.H. (RSG-12-158-01-DMC).

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