research
The DNA Replication Initiation Machinery as a Target for Cancer Diagnosis and Therapy
- Publication date
- 29 June 2011
- Publisher
- Cancer is a leading cause of death worldwide. Early, accurate detection of
malignancy leads to better treatment decisions and there is consequently
an urgent need for new cancer biomarkers. This thesis explores the use of
the DNA replication initiation machinery as a target for the development
of molecular biomarkers able to provide diagnostic and prognostic
information in the clinical setting and to guide treatment decisions. In a
large scale multicentre study, the DNA replicative helicase protein Mcm5
is shown to be a sensitive and specific biomarker for bladder cancer
detection. Further clinical studies demonstrate that Mcm5 is potentially
useful for the detection of prostate and pancreaticobiliary tract cancers.
In conjunction with markers of mitotic progression and DNA ploidy status,
replication initiation proteins are also shown to be able to provide
prognostic information in the context of penile cancer. Mcm5 is a
component of the DNA replicative helicase, which is phosphorylated by the
cell cycle kinase Cdc7 as a crucial step during DNA replication
initiation. The work described here demonstrates that depletion of Cdc7 in
a normal human diploid cell line induces a novel origin activation
checkpoint at the core of which there are a number of tumour suppressor
and proto-oncogene proteins that are freq