RIF1 regulates early replication timing in murine B cells
Daniel Malzl, Mihaela Peycheva, Ali Rahjouei, Stefano Gnan, Kyle N. Klein, Mariia Nazarova, Ursula E. Schoeberl, David M. Gilbert, Sara B.C. Buonomo, Michela Di Virgilio, Tobias Neumann, Rushad Pavri
Abstract
The mammalian DNA replication timing (RT) program is crucial for the proper functioning and integrity of the genome. The best-known mechanism for controlling RT is the suppression of late origins of replication in heterochromatin by RIF1. Here, we report that in antigen-activated, hypermutating murine B lymphocytes, RIF1 binds predominantly to early-replicating active chromatin and promotes early replication, but plays a minor role in regulating replication origin activity, gene expression and genome organization in B cells. Furthermore, we find that RIF1 functions in a complementary and non-epistatic manner with minichromosome maintenance (MCM) proteins to establish early RT signatures genome-wide and, specifically, to ensure the early replication of highly transcribed genes. These findings reveal additional layers of regulation within the B cell RT program, driven by the coordinated activity of RIF1 and MCM proteins.