title: Disruption of the Rev3l-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality.
abstract: Polymerase zeta (Pol zeta) is an error-prone DNA polymerase [1], which in yeast is involved in trans-lesion synthesis (TLS) and is responsible for most of the ultraviolet (UV) radiation-induced and spontaneous mutagenesis [2-4]. Pol zeta consists of three subunits: REV1, a deoxycytidyl-transferase [5]; REV7, of unclear function [6]; and REV3, the catalytic subunit. REV3 alone is sufficient to carry out TLS, but association with REV1 and REV7 enhances its activity [5, 7]. Experiments using human cells treated with UV radiation indicate also that mammalian Pol zeta is involved in TLS [7]. The peculiar mutagenic activity of Pol zeta [4,7,8] suggests a possible role in somatic hypermutation of immunoglobulin (Ig) genes [9]. Here, we report that, unlike in yeast where the REV3 gene is not essential for life [4], disruption of the mouse homologue (Rev3l) resulted in early embryonic lethality. In Rev3l(-/-) embryos, no haematopoietic cells other than erythrocytes could be identified in the yolk sac. Rev3l(-/-) haematopoietic precursors were unable to expand in vitro and no haematopoietic cells could be derived from the intraembryonic haematogenic compartment (splanchnopleura). Fibroblasts could not be derived from the Rev3l(-/-) embryos, and Rev3l(-/-) embryonic stem (ES) cells could not be obtained. This is the first evidence that an enzyme involved in TLS is critical for mammalian development.
authors.affiliation: Institute for Genetics, University of Cologne, Germany. gespisito@mac.genetik.uni-koeln.de
authors.forename: G
authors.initials: G
authors.lastname: Esposito
authors.forename: I
authors.initials: I
authors.lastname: Godindagger
authors.forename: U
authors.initials: U
authors.lastname: Klein
authors.forename: M L
authors.initials: ML
authors.lastname: Yaspo
authors.forename: A
authors.initials: A
authors.lastname: Cumano
authors.forename: K
authors.initials: K
authors.lastname: Rajewsky
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics*; D005804:Genes, Lethal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D004259:DNA-Directed DNA Polymerase; C092602:REV3 protein, S cerevisiae