Title: Understanding the Mechanism of Telomere Replication
Funder: Cancer Research UK

Abstract: Background A hallmark of cancer cells is an apparently limitless potential to divide. In eukaryotes, proliferative capacity is determined by telomeres, nucleoprotein structures that cap the chromosome end: telomere shortening during S-phase limits the number of times a cell can divide, and is prevented by the reverse transciptase telomerase, which lengthens the chromosome end. By controlling proliferative capacity in this way, telomeres are central to the development and progression of cancer, and more than 90 % of all cancer cells overexpress telomerase in order to divide indefinitely. Telomere length is established during a process called telomere replication, in which the ends of eukaryotic chromosomes are duplicated, resected and extended each S-phase. Whilst genetic studies have identified many of the key players in this process, we currently lack an integrated, mechanistic understanding of how telomeres are faithfully inherited from one generation to the next. Given the central role of these structures in human health and disease, a molecular understanding of telomere replication is crucial. Aims I will use a multidisciplinary approach to develop a mechanistic picture of telomere replication, addressing three complementary aims: 1. I will determine how telomeres are replicated semiconservatively, establishing the telomeric structures and properties that impede replication, and how they are overcome. 2. I will elucidate how DNA replication terminates at the very end of the chromosome, providing molecular insight into telomere shortening during this process. 3. I will examine how telomeres are resected and extended, providing mechanistic insight into the regulation of telomere length. Methods I will use cutting edge biochemical and structural techniques, complemented by genetic approaches. The starting point for my work is a recently reconstituted assay for eukaryotic DNA replication, which I will use in combination with reconstituted telomeric templates to study telomere replication and processing in vitro. This novel approach will allow me to carry out a molecular dissection of these steps, establishing a detailed mechanistic picture of how telomere biogenesis takes place. How the results of this research will be used. My research will enhance our fundamental understanding of the processes that define the structure and function of telomeres, providing insight into how complex substrates are copied by the replisome and replicated telomeres are resected and extended. In the longer term, this work will provide new opportunities to understand the role of telomeres in human diseases such as cancer.

Lay abstract: Background A hallmark of cancer cells is an apparently limitless potential to divide. In eukaryotes, proliferative capacity is determined by telomeres, nucleoprotein structures that cap the chromosome end: telomere shortening during S-phase limits the number of times a cell can divide, and is prevented by the reverse transciptase telomerase, which lengthens the chromosome end. By controlling proliferative capacity in this way, telomeres are central to the development and progression of cancer, and more than 90 % of all cancer cells overexpress telomerase in order to divide indefinitely. Telomere length is established during a process called telomere replication, in which the ends of eukaryotic chromosomes are duplicated, resected and extended each S-phase. Whilst genetic studies have identified many of the key players in this process, we currently lack an integrated, mechanistic understanding of how telomeres are faithfully inherited from one generation to the next. Given the central role of these structures in human health and disease, a molecular understanding of telomere replication is crucial. Aims I will use a multidisciplinary approach to develop a mechanistic picture of telomere replication, addressing three complementary aims: 1. I will determine how telomeres are replicated semiconservatively, establishing the telomeric structures and properties that impede replication, and how they are overcome. 2. I will elucidate how DNA replication terminates at the very end of the chromosome, providing molecular insight into telomere shortening during this process. 3. I will examine how telomeres are resected and extended, providing mechanistic insight into the regulation of telomere length. Methods I will use cutting edge biochemical and structural techniques, complemented by genetic approaches. The starting point for my work is a recently reconstituted assay for eukaryotic DNA replication, which I will use in combination with reconstituted telomeric templates to study telomere replication and processing in vitro. This novel approach will allow me to carry out a molecular dissection of these steps, establishing a detailed mechanistic picture of how telomere biogenesis takes place. How the results of this research will be used. My research will enhance our fundamental understanding of the processes that define the structure and function of telomeres, providing insight into how complex substrates are copied by the replisome and replicated telomeres are resected and extended. In the longer term, this work will provide new opportunities to understand the role of telomeres in human diseases such as cancer.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE