Chemical protein polyubiquitination reveals the role of a noncanonical polyubiquitin chain in DNA damage tolerance.

Kun Yang, Ping Gong, Parikshit Gokhale, Zhihao Zhuang

ACS chemical biology 2014 Aug 15

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Polyubiquitination of proteins regulates a variety of cellular processes, including protein degradation, NF-κB pathway activation, apoptosis, and DNA damage tolerance. Methods for generating polyubiquitinated protein with defined ubiquitin chain linkage and length are needed for an in-depth molecular understanding of protein polyubiquitination. However, enzymatic protein polyubiquitination usually generates polyubiquitinated proteins with mixed chain lengths in a low yield. We report herein a new chemical approach for protein polyubiquitination with a defined ubiquitin chain length and linkage under a mild condition that preserves the native fold of the target protein. In DNA damage tolerance, K63-polyubiquitinated proliferating cell nuclear antigen (PCNA) plays an important yet unclear role in regulating the selection of the error-free over error-prone lesion bypass pathways. Using the chemically polyubiquitinated PCNA, we revealed a mechanism of the K63 polyubiquitin chain on PCNA in promoting the error-free lesion bypass by suppressing the DNA translesion synthesis (TLS).

Citation

Kun Yang, Ping Gong, Parikshit Gokhale, Zhihao Zhuang. Chemical protein polyubiquitination reveals the role of a noncanonical polyubiquitin chain in DNA damage tolerance. ACS chemical biology. 2014 Aug 15;9(8):1685-91