DNA replication and genome stability

Complete, accurate replication of the genome is crucial for life. Errors during DNA replication give rise to mutations that cause genetic disease; failures during genome replication directly underlie several human disorders. DNA replication is the direct target of many chemotherapeutic agents.

Origin detection by Nanopore sequencing

Genome replication seen by sequencing and single cell analysis

Molecular architecture and evolutionary conservation of a DNA replication origin

We use a variety of cellular, molecular, genomic, bio-informatic and modelling approaches to understand how DNA replication is regulated to ensure genome stability. By focusing on the basic biology that underpins cell growth and division, we envisage providing novel insights that will help our understanding of diseases such as cancer and congenital disorders.

Eukaryotes, including yeast and humans, have large genomes with millions of bases encoding the genetic information. To ensure complete replication of these genomes, the process of DNA replication starts at multiple sites along each chromosome, called replication origins. Failure to activate sufficient or appropriately-distributed origins can result in unreplicated regions of the genome, which cannot be properly segregated during cell division. To facilitate faithful replication, origins activate at characteristic times during S phase, resulting in genomes replicating in a highly conserved, characteristic temporal order. This is of critical importance, as illustrated by disruption of replication timing in cancer cells contributing to genome instability by leading to chromosome breaks, translocations and aneuploidy.

Our long-term research aims are to determine: i) how cells ensure that sufficient replication origins are activated to fully replicate the genome; ii) the mechanisms involved in faithfully completing genome replication; and, the physiological consequences of deregulated genome replication.

Relevant Publications

Müller, CA, Boemo, MA, Spingardi, P, Kessler, BM, Kriaucionis, S, Simpson, JT, Nieduszynski, CA.

Nat Methods 16: 429-436

Müller, CA, Nieduszynski, CA.

J. Cell Biol. 216:1907

Daigaku, Y, Keszthelyi, A, Müller, CA, Miyabe, I, Brooks, T, Retkute, R, Hubank, M, Nieduszynski, CA, Carr, AM.

Nat. Struct. Mol. Biol. 22: 192

Müller CA, Hawkins M, Retkute R, Malla S, Wilson R, Blythe M, Nakato R, Komata M, Shirahige K, Moura APS, Nieduszynski CA.

Nucleic Acids Research 42: e3

Research Areas