Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Regulated replication initiation in genome stability and development.

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £1.7M
Period Sept 2015 — Dec 2020

In plain English

AI plain-English summary

Every time a cell divides, it must copy its entire genome—and the timing of that copying is far from random. This project investigates how cells control the order in which DNA is replicated, and what happens when that order goes wrong. The problem is that disrupted replication timing is linked to cancer and ageing, yet scientists do not fully understand how replication control works in living organisms. Most studies have used cells in a dish, not whole animals. This research fills that gap by studying replication timing in two complementary systems: budding yeast, where the entire genome can be analysed, and frog embryos, where replication patterns change dramatically during development. This is fundamental science. It will not produce a new drug or diagnostic test tomorrow. But understanding how replication timing influences gene expression and genome stability could eventually explain why cancer cells reorder their replication schedules—and whether that reordering drives disease or is merely a symptom. Similar fundamental work on DNA replication control has already underpinned cancer therapies that target dividing cells. Deeper knowledge of the process may reveal new vulnerabilities in cancer cells or new ways to minimise the side effects of chemotherapy.

View original technical description
Accurate DNA replication is critical for normal cell proliferation. Deregulation of this process is linked to multiple human disorders, such as cancer and ageing and is a consequence of most chemotherapies [1-4]. My long-term goal is to understand DNA replication control during cell division and development. Since genome duplication mechanisms are conserved across eukaryotes, we use discoveries in budding yeast to generate novel insights into metazoan development (Collart et al 2013 Science, Gag gioli et al 2014 J Cell Biol). By investigating replication control in whole animals we will unlock new ways to study the causes and treatment of human diseases. The focus of this proposal is the role of the temporal control of genome duplication during S-phase. Replication timing patterns are regulated during development and differentiation [5, 6] and altered in cancer cells [7]. Our specific questions take advantage of the power of whole genome analysis in the budding yeast (S. cerevisiae) together with the dramatic developmental regulation of S-phase that occurs during the embryonic divisions of Xenopus laevis as follows: Q1. What is the direct role of replication regulation in gene expression? Q2. How are replication and gene expression changes coordinated during vertebrate embryogenesis? Q3. How does replication timing affect genome stability? These inter-related questions will address conserved roles for DNA replication control that are relevant to human diseases.

View the original record at the funder ↗

Researchers

Philip Zegerman (EPMC Awardee)

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Original classification

Senior Research Fellowship Basic

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.