The DNA damage response
Lead Research Organisation:
The Francis Crick Institute
Abstract
Our DNA, which encodes the blue print of life, is under constant assault from both external and internal sources. UV light from the sun and ionizing radiation, as well as by-products of cellular metabolism, can induce a range of complex lesions in DNA that must be recognised and repaired correctly to prevent loss or alterations to the information encoded in DNA. Over the last 30 years it has emerged that many human genetic orders, which predispose to cancer and accelerated aging, result from defects in key DNA repair genes. For example, defects in nucleotide excision repair that recognises and repairs UV damage in DNA, results in the skin cancer predisposition syndrome Xeroderma pigmentosm. The goal of my lab is to identify new DNA repair genes, understand how they work and are regulated in cells, how loss of these genes impacts on normal organismal development and how this is compromised in disease. To do this, my group exploits the power of genetics to conduct screens for new DNA repair genes. This is complemented with biochemical methods that allow us to identity where the proteins operate in the cell and who they work with. It is hoped that that our work will provide an improved understanding of how DNA repair works and how, when DNA repair is compromised, it contributes to cancer/ageing and or infertility disorders in humans.
Technical Summary
This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)
DNA is a highly reactive molecule that is susceptible to damage. Fortunately, cells have evolved specialized repair processes that are remarkably efficient in correcting specific types of DNA damage. Failure to correctly repair DNA damage can drive mutagenic change, which can contribute to ageing and cancer. Indeed, defects in genes that repair DNA damage are the underlying cause of a number of hereditary ageing/cancer predisposition syndromes such as Fanconi anemia and Blooms.
Arguably the most toxic DNA lesion in cells occurs when both strands of the DNA duplex is severed to produce a DNA double strand break (DSBs). These lesions can arise as a result of exogenous insults (such as exposure to ionizing radiation) but also occur endogenously from the collapse of replication forks. Moreover, programmed DSB are essential for generating the immune system during V(D)J and CSR recombination and for producing viable gametes for sexual reproduction during meiosis. Aberrant repair of mitotic DSBs is believed to be the major source of translocations and other complex structural variations in cancer whereas defects in meiotic DSB repair are a source of infertility in humans.
My lab exploits a range of complementary experimental approaches to identify new DSB repair genes, define how they work in cells and the whole organism and operate at a molecular level. This includes genetic and phenotypic studies in C. elegans, mouse and human cells, proteomic approaches, biochemistry, single molecule biophysics and structural studies. We are particularly interested in the regulation and execution of DSB repair during DNA replication, meiosis and at telomeres and have established cutting-edge proteomic methods to identify novel factors that respond to and deal with stalled/reversed replication forks and dysfunctional telomeres. New factors that we have identified are often mutated in human diseases.
We hope that our work will provide an improved understanding of how DNA repair works and how, when DNA repair is compromised, it contributes to cancer/ageing and or infertility disorders in humans.
DNA is a highly reactive molecule that is susceptible to damage. Fortunately, cells have evolved specialized repair processes that are remarkably efficient in correcting specific types of DNA damage. Failure to correctly repair DNA damage can drive mutagenic change, which can contribute to ageing and cancer. Indeed, defects in genes that repair DNA damage are the underlying cause of a number of hereditary ageing/cancer predisposition syndromes such as Fanconi anemia and Blooms.
Arguably the most toxic DNA lesion in cells occurs when both strands of the DNA duplex is severed to produce a DNA double strand break (DSBs). These lesions can arise as a result of exogenous insults (such as exposure to ionizing radiation) but also occur endogenously from the collapse of replication forks. Moreover, programmed DSB are essential for generating the immune system during V(D)J and CSR recombination and for producing viable gametes for sexual reproduction during meiosis. Aberrant repair of mitotic DSBs is believed to be the major source of translocations and other complex structural variations in cancer whereas defects in meiotic DSB repair are a source of infertility in humans.
My lab exploits a range of complementary experimental approaches to identify new DSB repair genes, define how they work in cells and the whole organism and operate at a molecular level. This includes genetic and phenotypic studies in C. elegans, mouse and human cells, proteomic approaches, biochemistry, single molecule biophysics and structural studies. We are particularly interested in the regulation and execution of DSB repair during DNA replication, meiosis and at telomeres and have established cutting-edge proteomic methods to identify novel factors that respond to and deal with stalled/reversed replication forks and dysfunctional telomeres. New factors that we have identified are often mutated in human diseases.
We hope that our work will provide an improved understanding of how DNA repair works and how, when DNA repair is compromised, it contributes to cancer/ageing and or infertility disorders in humans.
