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Genomic Instability:Signaling Pathways Orchestrating the Responsesto Ionizing Radiation and Cisplatin

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Genome Integrity

Part of the book series: Genome Dynamics and Stability ((GENOME,volume 1))

Abstract

Eukaryotic cells have developed several types of cellular defense mechanisms in the face of injuries caused by a variety of genotoxic agents. Each type of DNA lesion can be recognized and processed by specialized repair pathways. Although the signaling responses to ionizing radiation (IR) and the cross-linking drug cisplatin have been extensively studied in different cell types, the mechanisms are still unclear. Following IR, the ATM-CHK2 pathway is preferentially activated, while the ATR-CHK1 seems to be the alternative pathway in response to cisplatin treatment, similarly to UV-light exposure. While NER (nucleotide excision repair) and HR (homologous recombination) seem to constitute the main repair processes for cisplatin-induced DNA-adducts, HR and NHEJ (non-homologous end-joining) are important mechanisms for radiation-induced DSB repair; in addition, IR-induced oxidative damage can be repaired by NER and BER pathways. IR and cisplatin induce cell cycle arrest in all phases, while the induction of apoptosis mainly depends on the cell type and treatment conditions. It is still unclear how these processes act in concert, in spite of a considerable body of information in the literature that has emerged in the last decade. The data regarding gene expression analyzed at transcription level associated to cellular endpoints may indicate at least some interconnection among DNA repair, cell-cycle checkpoints and apoptosis. All these studies have been carried out in normal cells, with the aim of clarifying the mechanisms leading to genomic instability and carcinogenesis, in contrast to those performed in tumor cells, which are relevant for understanding drug or IR responses towards improvement in therapeutic strategies.

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Acknowledgments

The authors would like to thank all members and collaborators of the laboratories involved in the work on gene expression, in particular, Dr Cristina M. Junta, Dr Paula Sandrin-Garcia and Dr Renato S. Cardoso. The research Grant from FAPESP, CNPq, CAPES and FAEPA (HC-FMRP, USP) is also acknowledged. The authors also apologize to those investigators whose articles were not cited due to space constraints.

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  1. Departamento de Biologia, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Ribeirão Preto, SP, Brazil

    Elza T. Sakamoto-Hojo

  2. Departamento de Genética, Ribeirão Preto, SP, Brazil

    Elza T. Sakamoto-Hojo, Stephano S. Mello, Carmen L. Bassi, Igor M. Merchi, Patricia O. Carminati, Ana L. Fachin & Geraldo A. S. Passos

  3. Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil

    Eduardo A. Donadi

  4. Faculdade de Odontologia de Ribeirão Preto, Universidade São Paulo (USP), Ribeirão Preto, SP, Brazil

    Geraldo A. S. Passos

  5. Departamento Biologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade São Paulo (USP), Av. Bandeirantes 3900, 14040-901, Ribeirão Preto, SP, Brazil

    Elza T. Sakamoto-Hojo

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Sakamoto-Hojo, E.T. et al. (2005). Genomic Instability:Signaling Pathways Orchestrating the Responsesto Ionizing Radiation and Cisplatin. In: Lankenau, DH. (eds) Genome Integrity. Genome Dynamics and Stability, vol 1. Springer, Berlin, Heidelberg . https://doi.org/10.1007/7050_010

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