Disruption of the Rev3l-encoded catalytic subunit of polymerase ζ in mice results in early embryonic lethality

Polymerase zeta>(*) over bar * (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 Pl 5 is involved in TLS [7], The peculiar mutagenic activity of Pol zeta [4,7,8] suggests a possible role in somatic hypermutation of immunoglobulin tig) genes [9]. Here, we report that, unlike in yeast where the REV3 gene is not essential for life [4], disruption of the mouse homologue (Rev31) resulted in early embryonic lethality, In Rev31(-/-) embryos, no haematopoietic cells other than erythrocytes could be identified in the yolk sac, Rev31(-/-) 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 Rev31(-/-) embryos, and Rev31(-/-) embryonic stem (ES) cells could not be obtained. This is the first evidence that an enzyme involved in TLS is critical for mammalian development. (C) 2000 Elsevier Science Ltd. All rights reserved.