Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro

Multiple DNA polymerases exist in eukaryotes, Polymerases alpha,delta and e psilon are mainly responsible for chromosomal DNA replication in the nucleu s and are required for proliferation. In contrast, the repair polymerases b eta and eta are not essential for cellular proliferation in yeast or mice, but a lack of either polymerase can lead, respectively, to defects in base excision repair or the ability to replicate past lesions induced by ultravi olet (UV) radiation [1-3]. Here, we have focused on polymerase zeta. This w as first described as a non-essential product of the yeast REV3/REV7 genes involved in UV induced mutagenesis, and was later implicated in trans-lesio n synthesis [4,5], Unlike in yeast, the mouse homologue (mRev3) was found t o be essential for life. Homozygous mutant mice died in utero. Mutant embry os were considerably reduced in size at day 10.5 of development and usually aborted around day 12.5, It is likely that this block reflects a need for mRev3 in proliferative clonal expansion (rather than in the production of a particular cell type) as mutant blastocysts showed greatly diminished expa nsion of the inner cell mass in culture. Thus, mRev3 could be required to r epair a form of externally induced DNA damage that otherwise accumulates du ring clonal expansion or, consistent with the high homology shared between its Rev7 partner and the mitotic checkpoint gene product Mad2 [6], mRev3 mi ght play a role in cell proliferation and genomic stability even in the abs ence of environmentally induced damage, (C) 2000 Elsevier Science Ltd. All rights reserved.