Induction, repair and biological consequences of DNA damages caused by radiations of various qualities

Project Information

RADNA

Grant agreement ID: FIGH-CT-1999-00012

Project closed

Start date 1 February 2000

End date 31 July 2003

Funded under

• Research and training programme (Euratom) in the field of nuclear energy (1998 to 2002)

Total cost

€ 1 276 209,00

EU contribution

€ 1 075 000,00

Coordinated by

GRAY LABORATORY CANCER RESEARCH TRUST
United Kingdom

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Deliverables

Mutation induction

Main results are: - Non-contiguous deletions, consistent with chromosome level (small fragments) LET dependence. - Deletion patterns reflect cell type? Future study. - Little difference in lesion spectrum in repair inhibited cells (although differences in mutation yields). - Heterogeneous distribution of damage at lung branch points and modelling of activity distribution. - Alpha and neutron induced radio adaptation have been measured also in bystandar cells.

Mechanisms of chromosome aberration formation

Main results are: - Evidence for lesion non-lesion interaction. - Evidence for a single-hit formation of chromatid breaks. - Development of a model of fast local chromatin denaturation. - Previously unknown complexity of chromosome aberrations using developments of FISH technologies potential future signatures of exposure. - Experimental data from RGL validating Cremer hypothesis for formation of exchanges.

Development of microbeams

Main results are: - Increase of European competence with technology transfer between partners, two new microbeams (and other outside contract) Increase range of radiations (low- (e.g., fast protons, focused x-rays) to high-LET), accuracy and approaches. - Importance of cellular signalling at individual cell level, identify source and receptor of signal. Sub-cellular precision (e.g., cytoplasmic versus nuclear targeting). Window on how organised tissues respond. Low dose risk of single tracks and individual electrons. - Therapy relevance: Potential to test for modulation of radiation effects and signal transduction pathways in tumours and normal tissues by modifiers of radiation effects. - Development of ideas of relationships of bystander and adaptive responses.

Rejoining and repair fidelity of DNA

Main results are: - Evolution of activities from previous contracts. - Importance of repair and influence of complexity of reparability for different radiations. - Differences between correct rejoining and misrepair. - Differences between low-dose rate and acute exposure versus radiation quality - evidence for intra-track misrepair, increasing with LET. - HR and NHEJ both contribute considerably to the repair of IR-induced DSBs in G2, whereas HR appears to play no major role in situations where no sister chromatid is available. Number of breaks determines mis-rejoining frequencies for low LET radiation (spatial proximity). - Importance of clustered damage. - Role of different repair pathways. Spontaneously induced breaks (S-phase) repaired exclusively by HR (associated with replication forks), radiation uses NHEJ. - NHEJ important for correct rejoining of complex breaks. - Improved measure of kinetics of repair (Heat labile) less repair in NHEJ mutants.

DNA dsb induction and distributions

Main results are: - Ability to measure DNA damage at lowest possible dose (low LET) and at the level of single particle traversals. - Developed and refined assays for dsb studied with respect to radiation quality (evolving from earlier contracts). - Improvements in measurements of yields of dsb with respect to improvements in PFGE analysis (heat labile and background). Understanding of track-correlated breaks. Development of analytical models to simulate break distributions and allow for background breaks. Quantitative description of clustering process. Extrapolation to low doses (ãH2AX). Measurement of breaks at ~1 electron track per cell and with <1dsb (average) per cell.

Publications

Other (1)

Induction, repair and biological consequences of DNA damages caused by radiations of various qualities (RADNA)

Author(s): MICHAEL B D (Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood (GB))
Published in: A project summary published in a DG Research brochure: "Understanding the effects of radiation on health". EUR 19959. Luxembourg, EUR-OP, 2002. pp.16-17, 2002, Page(s) 16-17, ISBN 92-894-3840-1