Uncovering the role of RNA in the initiation of genome replication

Resumen

To ensure lineage integrity, cells need to coordinate the activation of multiple DNA replication origins dispersed throughout their genome. While transcriptional activity and linked epigenetic factors are known to regulate origin formation and activation in human cells, little is known about the putative role of RNAs in this process, although they have been extensively reported to regulate chromatin fate through a variety of mechanisms provided by their versatile nature. In this work, we have identified a list of RNA interactors of ORC1, the largest subunit of the human Origin Recognition Complex, driving origin selection. Coupled to the characterization of ORC1 RNA-binding mutant, as well as diverse locus-specific and genome-wide in silico and experimental approaches, we show that ORC1 binding to RNA regulates origin activity in human cells. Remarkably, ORC1 RNA-binding functionality expands to the control of centrosome copy number, highlighting the extent of RNA-dependent regulatory functions needed for genomic stability.