David Melton - Overview

We are studying the relationship between DNA repair deficiency and cancer susceptibility using transgenic models for human inherited diseases such as xeroderma pigmentosum and Bloom's Syndrome where there is genome instability and a high incidence of cancer. The expression and role of the ERCC1 gene in the nucleotide excision repair process, which protects the skin from ultra violet light-induced DNA damage, is being studied. In addition, we are investigating the importance of ERCC1 in nucleotide excision repair and recombinational repair pathways for endogenous DNA damage in internal tissues. The link between ERCC1 deficiency and premature ageing, cell cycle arrest and genome instability is being investigated in the liver where ERCC1 deficiency causes the premature development of polyploidy. Transgenic models with a point mutation in the DNA ligase I gene, which is responsible for joining short intermediates during DNA replication, have defects in haematopoiesis and an elevated incidence of both haematopoietic and epithelial cancers. The models are being used to study the relationship between DNA replication, genome instability, apoptosis and cancer. Complete nucleotide excision repair deficiency, as found in the rare disease xeroderma pigmentosum, causes a thousand-fold increased incidence in skin cancer. We are studying the role of nucleotide excision repair gene polymorphisms as genetic risk factors for melanoma in the general population in Scotland where the frequency of this form of skin cancer is particularly high and rising.