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Molecular control of DNA replication timing in mammalian cells

Objective

DNA replication is an essential process ensuring the transmission of genetic information and is highly regulated. Specifically, the DNA replication-timing program ensures that the sites of initiation of DNA replication, termed origins, are not all activated simultaneously but follow a cell-type specific schedule. This pathway is conserved throughout eukaryotic evolution, however its molecular control and biological role are not fully understood. In this proposal I aim to understand key aspects of replication-timing program by employing a combination of advanced mouse genetics, genomics, cell biology and proteomics. Currently one of the major limitations in the mammalian DNA replication field is the elusive identity of origins. I aim to comprehensively map origins in a variety of mouse cells/tissues and relate the regulation of origin firing to the control of gene expression and three-dimensional nuclear architecture. I have discovered that Rif1 controls replication timing and links it to nuclear three-dimensional organization. I have also revealed the existence of a novel Rif1-independent pathway that controls the timing of a significant fraction of the late-replicating genome, identified by constitutive association with a key nuclear architecture component, Lamin B1. Here, I propose complementary approaches to understand the molecular mechanism by which Rif1 coordinates replication timing and nuclear organization as well as the molecular underpinnings of the novel pathway instructing late-replication in Lamin B1-associated regions. Finally, my goal is to understand the in vivo biological role of the replication-timing program. Our preliminary data identify mammalian X inactivation as a process where replication timing may play a fundamental part. My ultimate objective is to contribute to the realization of a comprehensive understanding of nuclear function, integrating the co-regulation of DNA replication with gene expression, epigenetic inheritance and DNA repair.

Call for proposal

ERC-2016-COG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

THE UNIVERSITY OF EDINBURGH
Address
Old College, South Bridge
EH8 9YL Edinburgh
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 999 784,99

Beneficiaries (1)

THE UNIVERSITY OF EDINBURGH
United Kingdom
EU contribution
€ 1 999 784,99
Address
Old College, South Bridge
EH8 9YL Edinburgh
Activity type
Higher or Secondary Education Establishments