Multifaceted Recognition of Vertebrate Rev1 by Translesion Polymerases ζ and κ

Abstract

Background: Translesion synthesis requires the scaffolding function of the Rev1 CTD. Results: We determined the structures of the Rev1 CTD and its complex with Pol and mapped its Rev7-binding surface. Conclusion: Distinct surfaces of the Rev1 CTD separately mediate the assembly of extension and insertion translesion polymerase complexes. Significance: Cancer therapeutics could be developed by inhibiting Rev1 CTD-mediated translesion synthesis.

Structural Basis of Recruitment of DNA Polymerase ζ by Interaction between REV1 and REV7 Proteins

“…5). Yeast two-hybrid assay predicted that a region between ␣B R1 and ␣C R1 of mouse Rev1 is important for interaction with mouse Rev7 (27). Our structure reveals that the ␤-sheet of REV7 interacts with the region between ␣B R1 and ␣C R1 , and the C-terminal region of REV1 follows ␣D R1 .…”

“…Implication for Polymerase Switching-While this manuscript was in preparation, NMR structures of the human REV1 C-terminal domain in complex with REV1-interacting region (RIR) peptides of human Pol (amino acids 524 -539) and the mouse Rev1 C-terminal domain in complex with a RIR peptide of mouse Pol (amino acids 560 -582) were reported (26,27). The structures reveal that the RIR forms a helical structure and binds to a hydrophobic surface composed of ␣A R1 and ␣B…”

Structural Basis of Rev1-mediated Assembly of a Quaternary Vertebrate Translesion Polymerase Complex Consisting of Rev1, Heterodimeric Polymerase (Pol) ζ, and Pol κ

“…3A, gray) (20), folds into a ␤-hairpin over the surface area between helices ␣1 and ␣2 of the Rev1 CTD and creates a deep hydrophobic pocket to interact with Phe-566 and Phe-567, two invariant phenylalanine residues of the bindinginduced Pol RIR helix. The observation of extensive van der Waals interactions between these two phenylalanine residues and hydrophobic residues of the Rev1 CTD from the N-terminal loop (Ala-1158 and Leu-1169), the ␣1 helix (Leu-1169, Leu-1170, and Trp-1173), the ␣1-␣2 loop (Ile-1177), and the ␣2 helix (Val-1188) nicely supports our previously reported solution structure of the Rev1 CTD-Pol RIR complex (Fig.…”

“…We and others have recently reported the solution structures of the mouse and human Rev1 CTD and their complexes with the RIR peptides of Pol and Pol (20,21). Using yeast twohybrid assays, we have also mapped the Rev1 surface responsible for interaction with the Rev7 subunit of Pol .…”

RAD18 polymorphisms are associated with platinum-based chemotherapy toxicity in Chinese patients with non-small cell lung cancer

“…Hence, TLS may be regarded as a double-edged sword because translesion synthesis polymerases have a high tendency to introduce mutations at the sites of lesions in the extension step. These mutations might lead to platinum-chemotherapy resistance [17][18][19] and side effects.…”