Structural basis of ubiquitin recognition by translesion synthesis DNA polymerase ι

Biochemistry. 2010 Nov 30;49(47):10198-207. doi: 10.1021/bi101303t. Epub 2010 Nov 4.

Abstract

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 Polι. Using NMR spectroscopy, we have determined the structure of a complex of human Polι 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 Polι UBM2. Instead, binding of UBM2 is centered on the recognition of Leu8 in ubiquitin, which is essential for the interaction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • DNA Damage
  • DNA Polymerase iota
  • DNA Repair*
  • DNA Replication
  • DNA-Directed DNA Polymerase / metabolism*
  • Humans
  • Models, Molecular
  • Nuclear Proteins / metabolism*
  • Nucleotidyltransferases / metabolism*
  • Structure-Activity Relationship
  • Ubiquitin / metabolism*
  • Ubiquitination

Substances

  • Nuclear Proteins
  • Ubiquitin
  • Nucleotidyltransferases
  • REV1 protein, human
  • DNA-Directed DNA Polymerase
  • DNA Polymerase iota
  • POLI protein, human

Associated data

  • PDB/2KTF
  • PDB/2L0F
  • PDB/2L0G