A single aspartate mutation in the conserved catalytic site of Rev3L generates a hypomorphic phenotype in vivo and in vitro

Rémi Fritzen, Frédéric Delbos, Annie De Smet, Benoît Palancade, Christine E Canman, Said Aoufouchi, Jean-Claude Weill, Claude-Agnès Reynaud, Sébastien Storck

Research output: Contribution to journalArticlepeer-review

Abstract

Rev3, the catalytic subunit of yeast DNA polymerase ζ, is required for UV resistance and UV-induced mutagenesis, while its mammalian ortholog, REV3L, plays further vital roles in cell proliferation and embryonic development. To assess the contribution of REV3L catalytic activity to its in vivo function, we generated mutant mouse strains in which one or two Ala residues were substituted to the Asp of the invariant catalytic YGDTDS motif. The simultaneous mutation of both Asp (ATA) phenocopies the Rev3l knockout, which proves that the catalytic activity is mandatory for the vital functions of Rev3L, as reported recently. Surprisingly, although the mutation of the first Asp severely impairs the enzymatic activity of other B-family DNA polymerases, the corresponding mutation of Rev3 (ATD) is hypomorphic in yeast and mouse, as it does not affect viability and proliferation and moderately impacts UVC-induced cell death and mutagenesis. Interestingly, Rev3l hypomorphic mutant mice display a distinct, albeit modest, alteration of the immunoglobulin gene mutation spectrum at G-C base pairs, further documenting its role in this process.

Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalDNA Repair
Volume46
Early online date25 Jul 2016
DOIs
Publication statusPublished - Oct 2016

Keywords

  • DNA damage
  • Rev3I
  • DNA polymerase zeta
  • Translesion
  • Somatic hypermutation

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