Structural basis of ubiquitin recognition by translesion synthesis DNA polymerase ℓ

Gaofeng Cui, Robert C. Benirschke, Han Fang Tuan, Nenad Juranić, Slobodan MacUra, Maria Victoria Botuyan, Georges Mer

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Cells have evolved mutagenic bypass mechanisms that prevent stalling of the replication machinery at DNA lesions. This process, translesion DNA synthesis (TLS), involves switching from high-fidelity DNA polymerases to specialized DNA polymerases that replicate through a variety of DNA lesions. In eukaryotes, polymerase switching during TLS is regulated by the DNA damage-triggered monoubiquitylation of PCNA. How the switch operates is unknown, but all TLS polymerases of the so-called Y-family possess PCNA and ubiquitin-binding domains that are important for their function. To gain insight into the structural mechanisms underlying the regulation of TLS by ubiquitylation, we have probed the interaction of ubiquitin with a conserved ubiquitin-binding motif (UBM2) of Y-family polymerase Polℓ. Using NMR spectroscopy, we have determined the structure of a complex of human Polℓ UBM2 and ubiquitin, revealing a novel ubiquitin recognition fold consisting of two α-helices separated by a central trans-proline residue conserved in all UBMs. We show that, different from the majority of ubiquitin complexes characterized to date, ubiquitin residue Ile44 only plays a modest role in the association of ubiquitin with Polℓ UBM2. Instead, binding of UBM2 is centered on the recognition of Leu8 in ubiquitin, which is essential for the interaction.

Original languageEnglish (US)
Pages (from-to)10198-10207
Number of pages10
Issue number47
StatePublished - Nov 30 2010

ASJC Scopus subject areas

  • Biochemistry


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