Completed Genetics & Molecular Biology Cancer

DNA damage responses in mammalian cells and their contribution to human health disorders

Funder MRC (part of UKRI)
Recipient organisation University of Sussex
Funding £1.5M
Period Sept 2006 — Sept 2011

In plain English

AI plain-English summary

Every day, the DNA in human cells suffers thousands of breaks, and this research focuses on how cells repair the most dangerous type—double strand breaks—and what happens when those repairs fail. These breaks can be lethal or cause cancer. They arise from normal metabolism, from the immune system's own development process, and from radiation exposure. The body has two main repair pathways—non-homologous end-joining (NHEJ) and homologous recombination—plus a signalling system controlled by a protein called ATM. When NHEJ fails, the result is immunodeficiency and radiation sensitivity, as seen in three known human disorders. A separate signalling pathway, controlled by ATR, handles damage from stalled replication forks and is defective in Seckel Syndrome, though not all the faulty genes have been found. This is fundamental science. The programme aims to understand exactly how these repair and signalling mechanisms work at the molecular level, particularly the roles of the nuclease Artemis and the ATM and ATR proteins. There is no immediate practical application. However, deeper knowledge of these pathways could eventually inform treatments for immune disorders, cancer therapies that exploit repair weaknesses, or strategies to protect people from radiation damage—much as past fundamental work on DNA repair underpinned modern cancer drugs.

View original technical description
DNA damage responses encompass DNA repair processes and signal transduction mechanisms. The grant focuses on the response to DNA double strand breaks (DSBs), an important lethal and carcinogenic lesion. DSBs arise from endogenous oxidative damage, during certain metabolic processes including V(D)J recombination, a step during immune development, and following exposure to ionising radiation. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent DSB repair pathways and Ataxia telangiectasia mutated (ATM) regulates the major DSB signalling response. This programme aims to understand how DSBs are processed and rejoined by NHEJ and its contribution to human disease. Three disorders conferred by defects in NHEJ have known and all are associated with immunodeficiency and radiosensitivity. ATM signalling is dispensable for most DSB repair. However, a subset of DSBs require ATM signalling proteins and a nuclease, Artemis. We will examine the roles of Artemis and ATM in DSB repair. ATR regulates a related signalling process that is activated by stalled replication forks and bulky lesions. Seckel Syndrome is characterised by defects in the ATR signalling pathway, although not all defective genes have been identified. This programme will also aim to gain insight into ATR signalling and its contribution to disorders affecting human health.

View the original record at the funder ↗

Researchers

Penny Jeggo (Principal Investigator)

Related Research

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Understanding the wider biological impacts of impaired ATR-ATM DNA damage response pathway function upon signal transduction, cell cycle checkpoint control and DNA repair
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DNA damage responses in mammalian cells and their contribution to human health disorders; the end-stage.
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Original classification

Research Grant

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