Nicolas Lakin - Overview

Genomic DNA is continually being damaged by a variety of environmental agents such as UV and ionising radiation (IR), in addition to reactive oxygen species produced in the cell. The cell has therefore had to develop rapid and efficient mechanisms whereby it can detect, signal and repair DNA damage in order to maintain genome integrity. In recent years the importance of DNA damage signalling and repair has been highlighted by observations that mutations in genes involved in these pathways can lead to a variety of disease states including an increased risk of cancer. One example of this is ataxia-telangiectasia (A-T), a human autosomal recessive disorder characterised by neurological degeneration, immunological abnormalities, premature ageing, genomic instability, radiosensitivity and increased cancer incidence.

The product of the A-T gene (termed ATM) is a kinase critical for signalling DNA double strand breaks (DSBs) induced by agents such as IR. We and others have shown that ATM becomes activated in response to DNA DSBs and mediates the phosphorylation of a number of different effector molecules such as the tumour supressor protein p53. Furthermore, we have also shown that the ATM related kinase ATR phosphorylates p53 in a manner that is functionally overlapping but distinct from ATM. Indeed, the emerging picture is that whilst ATM signals DNA DSBs, ATR signals stalled replication forks, or other types of DNA damage induced by agents such as UV. Although the mechanisms of action of ATM and ATR are beginning to be elucidated, the precise modes of action of these critical kinases remain elusive. The main focus of the research in my laboratory is to use a combination of biochemistry and genetics to understand how ATM and ATR become activated and which proteins they phosphorylate and regulate in response to DNA damage. In addition to these studies, biochemical and genetic approaches are also being exploited to identifying novel genes that function in DNA damage signalling pathways. This work will provide an increased understanding of the mechanisms by which a cell detects and signals DNA damage, in addition to providing insights into the underlying cause of genetic diseases such as A-T. Furthermore, this research will contribute to a greater understanding of the molecular events that lead to the onset of oncogenesis.