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      DNA repair in cancer initiation, progression, and therapy—a double-edged sword

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          Abstract

          Genomic and mitochondrial DNA molecules are exposed continuously for a damaging activity of chemical, physical, and internal genotoxicants. When DNA repair machinery is not working efficiently, the generation of DNA lesions and mutations leads to carcinogenic transformation. The high number of mutation going up to 10 5 per cell was recognized as a driving force of oncogenesis. Moreover, a high activity of DNA repair genes was hypothesized as a predisposition to metastasis. DNA repair potential has to be taken into account attempting to chemo- and/or radiotherapy. A low activity of DNA repair genes makes tumor cells more sensitive to therapy, but on the other hand, non-tumor cells getting lesions could form second primary cancer. Contrary, high activity of DNA repair genes counteracts attempted therapy. It means an individualized therapy based on recognition of DNA repair potential is recommended.

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          Platinum resistance: the role of DNA repair pathways.

          Lainie Martin, Thomas Hamilton, Russell J Schilder (2008)
          Although platinum chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases, their efficacy in most cancers is limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. Recently acquired knowledge has provided insight into the molecular mechanisms of DNA repair pathways and their effect on response to chemotherapy. This review will discuss the most important DNA repair pathways known to be involved in the platinum response, i.e., nucleotide excision repair (NER) and mismatch repair (MMR), and will briefly touch on the role of BRCA in DNA repair. The therapeutic implications of alterations in DNA repair which affect response to platinum in the treatment of patients with malignant disease, such as excision repair cross-complementation group 1 (ERCC1) deficiency and mismatch repair deficiency, will be reviewed.
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            Targeting DNA damage response in cancer therapy

            Noriko Hosoya, Kiyoshi Miyagawa (2014)
            Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing DNA damage. DNA damage is normally recognized and repaired by the intrinsic DNA damage response machinery. If the damaged lesions are successfully repaired, the cells will survive. In order to specifically and effectively kill cancer cells by therapies that induce DNA damage, it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells. Such properties of cancer cells can provide biomarkers or targets for sensitization. For example, defects or upregulation of the specific pathways that recognize or repair specific types of DNA damage can serve as biomarkers of favorable or poor response to therapies that induce such types of DNA damage. Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA-damaging agents. Moreover, it may also be useful as a monotherapy when it achieves synthetic lethality, in which inhibition of a complementary DNA damage response pathway selectively kills cancer cells that have a defect in a particular DNA repair pathway. The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP-ribose) polymerase inhibitors. In this review, we describe the impact of targeting the cancer-specific aberrations in the DNA damage response by explaining how these treatment strategies are currently being evaluated in preclinical or clinical trials.
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              DNA damage response--a double-edged sword in cancer prevention and cancer therapy.

              Hui-yuan Tian, Zhen Gao, Huizhong Li … (2015)
              Genomic stability depends on an efficient DNA damage repair system to keep the chromosomes intact. Unrepaired DNA damage not only causes cell cycle arrest, apoptosis, but also accumulates genome mutations. DNA damage response (DDR) exhibits a critical function on the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DDR genes. However, a defective DNA repair is liked intimately with the unchecked proliferation and the intrinsic resistance to clinical DNA-damaging agents. Therefore, abrogation of specific proteins in DNA damage repair pathways is a promising strategy for developing targeted cancer treatments. It may sound paradoxical to inhibit DDR pathway for sensitization of clinical therapy because cancer promotion and malignant transformation are aided by deficient DNA repair pathways. Actually, DDR acts as a positive guardian of genomic stability to prevent from tumorigenesis. On the other hand, DDR also performs as a negative saboteur to resist chemo- and radiotherapy. In this regard, DDR functions as "a double-edged sword" in cancer prevention and cancer therapy. The defective DDR that makes cancer cells of high mutability should alternatively provide therapeutic opportunities that confer the lethality to cancer cells without harming normal cells.
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                Author and article information

                Contributors
                Katarzyna Kiwerska:
                ORCID: http://orcid.org/0000-0002-2319-0201
                +48 61 65 79 214 , katarzyna.kiwerska@igcz.poznan.pl
                Journal
                Journal ID (nlm-ta): J Appl Genet
                Journal ID (iso-abbrev): J. Appl. Genet
                Title: Journal of Applied Genetics
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 1234-1983
                ISSN (Electronic): 2190-3883
                Publication date (Electronic): 30 August 2019
                Publication date PMC-release: 30 August 2019
                Publication date (Print): 2019
                Volume: 60
                Issue: 3
                Pages: 329-334
                Affiliations
                GRID grid.413454.3, ISNI 0000 0001 1958 0162, Institute of Human Genetics, , Polish Academy of Sciences, ; Strzeszynska 32, 60-479 Poznan, Poland
                Author notes

                Communicated by: Michal Witt

                Author information
                http://orcid.org/0000-0002-2319-0201
                Article
                Publisher ID: 516
                DOI: 10.1007/s13353-019-00516-9
                PMC ID: 6803590
                PubMed ID: 31468363
                SO-VID: 7e1c1125-f458-44f5-8331-00c8feef8c51
                Copyright © © The Author(s) 2019
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 28 May 2019
                Date revision received : 25 July 2019
                Date accepted : 9 August 2019
                Funding
                Funded by: Institute of Human Genetics PAS
                Categories
                Subject: Human Genetics • Mini-Review
                Custom metadata
                issue-copyright-statement © Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2019

                ScienceOpen disciplines: Genetics
                Keywords: dna repair,polymorphism of dna repair genes,carcinogenesis,resistance to chemo- and radiotherapy
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: dna repair, polymorphism of dna repair genes, carcinogenesis, resistance to chemo- and radiotherapy

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