Cryptic redundancy between PAR1b and PAR1a, two members of the PAR1 kinase family, in the survival of PAR1b-knockout mice

The PAR1/MARK family of serine/threonine kinases (Par1a-d) redundantly regulates cell polarity. Furthermore, PAR1b facilitates nuclear translocation of BRCA1 through phosphorylation. Within the nucleus, BRCA1 protects stalled replication forks and repairs DNA double-strand breaks through homologous recombination. Consequently, BRCA1-knockout mice are embryonically lethal. In contrast, conventional PAR1b-knockout mice reach adulthood, suggesting a compensatory mechanism for PAR1b in regulating BRCA1 in these knockout mice. Here we find that while PAR1b knockout leads to the death of wild-type mouse embryonic fibroblasts (MEFs), PAR1b-null MEFs can be readily established from conventional PAR1b-knockout mice. In PAR1b-null MEFs from PAR1b-knockout mice, PAR1a, but not PAR1c or PAR1d, is essential for cell survival. Thus, PAR1a-mediated cryptic redundancy is unleashed only when functional PAR1b is absent from the onset of embryogenesis, which induces epigenetic changes in gene regulation. This study presents the first evidence of cryptic redundancy driven by epigenetic modifications in the regulation of gene expression during early embryogenesis. Overall design: ATAC-seq of mouse embryonic fibroblasts (MEFs) prepared from wild-type and conventional PAR1b-knockout mice