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 C. B. Buonomo, Michela Virgilio, Tobias Neumann () and Rushad Pavri ()
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Daniel Malzl: Research Institute of Molecular Pathology (IMP), Vienna Biocenter
Mihaela Peycheva: Research Institute of Molecular Pathology (IMP), Vienna Biocenter
Ali Rahjouei: Max-Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC)
Stefano Gnan: University of Edinburgh
Kyle N. Klein: San Diego Biomedical Research Institute
Mariia Nazarova: Research Institute of Molecular Pathology (IMP), Vienna Biocenter
Ursula E. Schoeberl: Research Institute of Molecular Pathology (IMP), Vienna Biocenter
David M. Gilbert: San Diego Biomedical Research Institute
Sara C. B. Buonomo: University of Edinburgh
Michela Virgilio: Max-Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC)
Tobias Neumann: Research Institute of Molecular Pathology (IMP), Vienna Biocenter
Rushad Pavri: Research Institute of Molecular Pathology (IMP), Vienna Biocenter

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43778-y

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