DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy - PubMed (original) (raw)

DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy

Emil Mladenov et al. Front Oncol. 2013.

Abstract

Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress - a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.

Keywords: DNA double-strand breaks; cancer; homologous recombination repair; ionizing radiation; radiosensitization.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Schematic representations of DSB repair by non-homologous end-joining. The process is initiated by the binding of KU heterodimer to the DNA ends, which then recruits DNA-PKcs to form an active DNA-PK holoenzyme. DNA-PK activation helps the recruitment of multiple proteins involved in the limited DNA end-processing (Artemis, pol μ, pol λ, and TDK) required to generate ligatable DNA ends. Ligation is mediated exclusively by the LIG4/XRCC4 complex and is assisted by the ligation mediator XLF. At the end of this process the DNA integrity at the break is restored, but the DNA sequence at the junction may be altered.

Figure 2

Figure 2

Repair of DSBs by B-NHEJ. This pathway remains incompletely characterized. Factors implicated include PARP-1, the MRN complex, CtIP, and WRN. Ligation is mediated by LIG3 or LIG1. The restoration of DNA integrity through this repair pathway is also associated with sequence information loss at the junction, and more importantly, by increased risk of joining unrelated DNA ends to generate translocations and other genomic rearrangements.

Figure 3

Figure 3

Schematic overview of the early steps of HRR. The formation of pre-synaptic Rad51 nucleoprotein filament. The initiation steps and the full sequence of events contributing to the faithful restoration of DNA sequence at the DSB are explained in the text.

Figure 4

Figure 4

Late steps in DSB repair by HRR. The formation of D-loop structure and two sub-pathways are depicted (see text for more details).

Figure 5

Figure 5

Post-translational modifications and interactions possibly involved in DSB repair pathway choice and HRR modulation. A network of proteins controls HRR and is regulated by cell-cycle dependent post-translational modifications. Cell-cycle regulation primarily relies on Cyclin/CDK dependent phosphorylation events. Regulation in response to DNA damage primarily relies on the activities of ATM, ATR, and DNA-PKcs. Control of end-resection plays a central role in this regulation. Resected DNA decorated with heterotrimeric RPA complexes forms a platform for activation of ATR. The schematic focuses on interactions/modifications implicated in the regulation of HRR.

References

    1. Adimoolam S., Sirisawad M., Chen J., Thiemann P., Ford J. M., Buggy J. J. (2007). HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc. Natl. Acad. Sci. U.S.A. 104, 19482–19487 10.1073/pnas.0707828104 - DOI - PMC - PubMed
    1. Ahmad S. S., Duke S., Jena R., Williams M. V., Burnet N. G. (2012). Advances in radiotherapy. BMJ 345, 33–38 10.1136/bmj.e7765 - DOI - PubMed
    1. Aly A., Ganesan S. (2011). BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. J. Mol. Cell Biol. 3, 66–74 10.1093/jmcb/mjq055 - DOI - PMC - PubMed
    1. Arias-Lopez C., Lazaro-Trueba I., Kerr P., Lord C. J., Dexter T., Iravani M., et al. (2006). p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene. EMBO Rep. 7, 219–224 10.1038/sj.embor.7400587 - DOI - PMC - PubMed
    1. Arosio D., Cui S., Ortega C., Chovanec M., Di Marco S., Baldini G., et al. (2002). Studies on the mode of Ku interaction with DNA. J. Biol. Chem. 277, 9741–9748 10.1074/jbc.M111916200 - DOI - PubMed

LinkOut - more resources