Metafork

With each division of eukaryotic cells, the chromosomes must be faithfully copied and transmitted from the mother cell to daughter cells as a whole entity; this includes the copying of genomic DNA and chromatin-based epigenetic components. It has been shown by us and by others, that DNA replication is intimately linked with epigenome replication. In particular, it has emerged that core DNA replication factors (e.g. MCM23), aside from their essential role in DNA synthesis, mediate faithful inheritance of histone marks. Another connection between DNA and epigenome replication is the binding of the DNA methylation maintenance enzymes to the replisome1. However, it remains unknown whether the DNA methylation machinery can regulate DNA replication, and whether impediments to DNA replication may misregulate DNA methylation. Our goal is to reveal how DNA replication forks coordinate the copying of genetic and epigenetic information in mammalian cells. Our specific aims are: (1) To reveal the role of DNA methylation machinery in DNA replication. (2) To understand how DNA replication forks coordinate both processes of DNA replication and DNA methylation maintenance. (3) To address how replicative stress impacts epigenome inheritance.