Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


TELOSENS Berichtzusammenfassung

Project ID: FIGH-CT-2002-00217
Gefördert unter: FP5-EAECTP C
Land: Germany

Ligase III: a role in a new NHEJ pathway to repair DNA double strand breaks?

Chromosome fusions are observed with high frequency in cells with defects in components of the standard pathway of DNA double strand break repair which suggests the operation of an alternative repair pathway that is capable of joining together eroded telomeric sequences when the canonical pathway is inactivated. Although DNA ligase III is predominantly considered a component of single strand break and base excision repair, our observations hint to a potential role in DNA DSB rejoining as well. DNA ligase III may be a bona fide component of DNA DSB repair by NHEJ, where it may function either alone or together with XRCC1 and PARP-1. This is in line with the ability of the purified enzyme to ligate plasmid DNA under physiological conditions and is directly supported by recent in vivo and in vitro results. Backup pathways of NHEJ operating independently of DNA ligase IV were also suggested by recent genetic experiments in Drosophila melanogaster and are shown to be involved in the repair of DSBs induced either after exposure to radiation. Evidence is thus mounting that NHEJ pathways operating independently of DNA-PK and DNA ligase IV operate in a variety of organisms.

The results presented allow the inference that these pathways of end joining will contribute significantly to the ability of cells of cope with radiation damage and should therefore contribute to their radioresistance to killing. However, because these pathways are error prone, they contribute to the development of cancer as well as to the fusion of chromosomes, particularly when telomeres erode. George Iliakis' work suggests that protection of chromosome ends from illegitimate end joining is likely mediated by the structure of the telomeres and the binding of specific proteins to telomeric sequences, rather than by an inherent inability of the NHEJ apparatus to deal with telomeric ends. Since end joining events containing telomeric regions could be observed under conditions where the canonical DNA end joining pathway is compromised by mutations either in components of DNA-PK (DNA-PKcs, KU70, KU80), as well as in DNA Ligase IV or XRCC4, G. Iliakis' team investigated in detail the possibility that backup pathways of NHEJ exist that may gain prominence in NHEJ mutants and may cause the genomic and telomeric instability observed.

These results are likely to have relevance in radiation protection as they identify pathways of repair that may contribute to tumorigenesis. Understanding therefore of the function of these pathways as well as of their relative contribution to the repair of DNA DSBs is likely to contribute to our understanding of cancer development under various conditions and treatments.

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