Research ArticleDNA Repair

K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair

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Science Signaling  05 Jun 2018:
Vol. 11, Issue 533, eaar8133
DOI: 10.1126/scisignal.aar8133

DNA-bound ubiquitin coordinates DNA repair

Ubiquitylation is a posttranslational modification that reversibly alters protein stability, activity, interactions, or trafficking. The ubiquitylation of histones and various other proteins facilitates the response to DNA damage. However, Liu et al. discovered that ubiquitin also binds directly to DNA. In solution and in live cells, chains of ubiquitin specifically linked through Lys63 residues (referred to as K63-linked polyubiquitin chains) preferentially bound to the free ends of double-stranded DNA through a three-amino acid motif in ubiquitin that the authors call a “DNA-interacting patch” (DIP). These chains appeared to bind the broken ends of DNA and recruit repair proteins. Ubiquitins with mutations in the DIP were found in several types of tumors and, when expressed in cultured cells, impaired the cellular response to DNA-damaging agents, suggesting that these mutations might be exploited for therapeutic benefit in some cancer patients.


Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys63 (K63) linkage bound to DNA through a motif we called the “DNA-interacting patch” (DIP), which is composed of the adjacent residues Thr9, Lys11, and Glu34. Upon DNA damage, the binding of K63-linked polyubiquitin chains to DNA enhanced the recruitment of repair factors through their interaction with an Ile44 patch in ubiquitin to facilitate DNA repair. Furthermore, experimental or cancer patient–derived mutations within the DIP impaired the DNA binding capacity of ubiquitin and subsequently attenuated K63-linked polyubiquitin chain accumulation at sites of DNA damage, thereby resulting in defective DNA repair and increased cellular sensitivity to DNA-damaging agents. Our results therefore highlight a critical physiological role for K63-linked polyubiquitin chains in binding to DNA to facilitate DNA damage repair.

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