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Enhancing radiotherapy through a greater understanding of homologous recombination.

ABSTRACT: Radiotherapy for the treatment of cancer can cause a wide range of cellular effects, the most biologically potent of which is the double-strand break in DNA. The process of repairing DNA double-strand breaks involves 1 of 2 major mechanisms: nonhomologous end joining or homologous recombination. In this review, we review the molecular mechanisms of homologous recombination, in particular as it relates to the repair of DNA damage from ionizing radiation. We also present specific situations in which homologous recombination may be dysfunctional in human cancers and how this functional abnormality can be recognized. We also discuss the therapeutic opportunities that can be exploited based on deficiencies in homologous recombination at various steps in the DNA repair pathway. Side-by-side with these potential therapeutic opportunities, we review the contemporary clinical trials in which strategies to exploit these defects in homologous recombination can be enhanced by the use of radiotherapy in conjunction with biologically targeted agents. We conclude that the field of radiation oncology has only scratched the surface of a potentially highly efficacious therapeutic strategy.

SUBMITTER: Barker CA

PROVIDER: S-EPMC4972489 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Enhancing radiotherapy through a greater understanding of homologous recombination.

Barker Christopher A CA Powell Simon N SN

Seminars in radiation oncology 20101001 4

Radiotherapy for the treatment of cancer can cause a wide range of cellular effects, the most biologically potent of which is the double-strand break in DNA. The process of repairing DNA double-strand breaks involves 1 of 2 major mechanisms: nonhomologous end joining or homologous recombination. In this review, we review the molecular mechanisms of homologous recombination, in particular as it relates to the repair of DNA damage from ionizing radiation. We also present specific situations in whi ...[more]

PMID: 20832019

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Project description:BackgroundIntrogression of a quantitative trait locus (QTL) by successive backcrosses is used to improve elite lines (recurrent parent) by introducing alleles from exotic material (donor parent). In the absence of selection, the proportion of the donor genome decreases by half at each generation. However, since selection is for the donor allele at the QTL, elimination of the donor genome around that QTL will be much slower than in the rest of the genome (i.e. linkage drag). Using markers to monitor the genome around the QTL and in the genetic background can accelerate the return to the recurrent parent genome. Successful introgression of a locus depends partly on the occurrence of crossovers at favorable positions. However, the number of crossovers per generation is limited and their distribution along the genome is heterogeneous. Recently, techniques have been developed to modify these two recombination parameters.ResultsIn this paper, we assess, by simulations in the context of Brassicaceae, the effect of increased recombination on the efficiency of introgression programs by studying the decrease in linkage drag and the recovery of the recurrent genome. The simulated selection schemes begin by two generations of foreground selection and continue with one or more generations of background selection. Our results show that, when the QTL is in a region that initially lacked crossovers, an increase in recombination rate can decrease linkage drag by nearly ten-fold after the foreground selection and improves the return to the recurrent parent. However, if the QTL is in a region that is already rich in crossovers, an increase in recombination rate is detrimental.ConclusionsDepending on the recombination rate in the region targeted for introgression, increasing it can be beneficial or detrimental. Thus, the simulations analysed in this paper help us understand how an increase in recombination rate can be beneficial. They also highlight the best methods that can be used to increase recombination rate, depending on the situation.

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Enhancing radiotherapy through a greater understanding of homologous recombination.

Publications

Enhancing radiotherapy through a greater understanding of homologous recombination.

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