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Symposium abstracts

DNA replication and cancer: lessons from budding yeast

John Diffley

CR-UK London Research Institute, UK

DNA replication plays an important role in cancer: errors during DNA replication generate the mutations required for cancer development, and a large number of anti-cancer drugs work by interfering with DNA replication.  A deeper understanding of the mechanism and regulation of DNA replication should provide targets for more efficient, less mutagenic anti-cancer drugs.

The large genomes of eukaryotic cells are replicated from multiple replication origins during S phase.  These origins are not activated synchronously at the beginning of S phase, but instead fire throughout S phase according to a pre-determined, cell type specific programme.   Only after the entire genome is completely replicated are cells allowed to proceed into mitosis.

Ensuring that each origin is efficiently activated once and only once during each S phase is crucial for maintaining the integrity of the genome.  This is achieved by a two-step mechanism.  The first step, known as licensing, involves the assembly of a pre-replicative complex (pre-RC) at replication origins. Pre-RCs, which contain the replicative DNA helicase (Mcm2-7) and are therefore essential for initiation, can only assemble at origins during G1 phase when cyclin dependent kinase (CDK) activity is low.  In the second step, CDKs trigger initiation by phosphorylating two essential proteins, Sld2 and Sld3.

I will present experiments using budding yeast showing that CDK deregulation, such as that seen in cancer, interferes with licensing, and promotes inappropriate entry into S phase. Subsequent DNA replication from an insufficient number of origins induces elevated levels of chromosome rearrangements. The mechanism by which this aberrant DNA replication leads to DNA damage and activation of DNA damage checkpoints will be discussed.   The subsequent loss of DNA damage checkpoints may be important to allow continued proliferation in the presence of DNA damage.  Loss of DNA damage checkpoints renders cells sensitive to DNA damaging agents including many well-known anti-cancer drugs, which may explain their initial efficacy.  We have found that subsequent loss of an enignaltic flap endonuclease, Exo1, can suppress this DNA damage sensitivity and we suggest this may be a mechanism by which cancer cells develop drug resistance.