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  • Introduction the DNA damage response important implications

    2023-01-24

    Introduction: the DNA damage response — important implications for tumour development and treatment Cells are invariably challenged by tens of thousands of lesions inflicted on their DNA everyday (Lindhal, 1993). This DNA damage can be caused exogenously by exposure to different types of radiation or genotoxic agents, or endogenously through, for example, racecadotril depurination and deamination or reactive by-products of cellular metabolism (Lindahl & Barnes, 2000). If unrepaired or aberrantly repaired, such lesions may prove lethal to the cell or give rise to deleterious mutations that can affect cell viability or induce aberrant cellular behaviour leading to the development of malignancies such as cancer. Because genetic alterations have such a significant potential impact on survival and viability of a cell, as well as the organism as a whole, cells have developed a complex network of signalling pathways – collectively known as the DNA damage response (DDR) – that orchestrates the detection and repair of DNA damage with transient cell cycle arrest to ensure maintenance of genomic stability and cell viability (Jackson and Bartek, 2010, Ciccia and Elledge, 2011). The DDR plays an important role in many aspects of cancer. First, deficiencies in DDR mechanisms have been shown to be contributing factors in many stages of tumour development. Numerous hereditary cancer predispositions result from mutations in DNA repair genes (Goode et al., 2002, Negrini et al., 2010). For example, women who carry a defective allele of the BRCA1 or BRCA2 genes, which encode for two proteins centrally involved in the repair of DNA double strand breaks (DSBs) by homologous recombination, are at much higher risk of developing breast and ovarian cancers than women in the general population (Pal et al., 2005, Levy-Lahad and Friedman, 2007). Furthermore, several studies have demonstrated activation of DDR proteins during early stages of tumourigenesis (Bartkova et al., 2005, Gorgoulis et al., 2005). This response has been linked to the induction of replication stress and DNA damage, caused by abnormal replication due to aberrant oncogene activation (Bartkova et al., 2006, Di Micco et al., 2006). It has been suggested that this activation of DDR pathways may limit tumour development in its early stages by acting as a barrier for proliferation of aberrant cells (Bartkova et al., 2005, Gorgoulis et al., 2005), particularly through activation of the tumour suppressor protein p53 (Halazonetis et al., 2008). Therefore, it is unsurprising that many malignant tumours show functional loss or deregulation of key proteins involved in the DDR and cell cycle regulation, most notably p53 and ATM (Cancer Genome Atlas Research Network, 2012a, Cancer Genome Atlas Research Network, 2012b, Cancer Genome Atlas Research Network, 2012c, Cancer Genome Atlas Research Network, 2014, Kandoth et al., 2013), MRE11 (Ottini et al., 2004, Bartkova et al., 2008, Choudhury et al., 2010), BRCA1/2 (Cancer Genome Atlas Research Network, 2012c, Kandoth et al., 2013) or SMC1 (Kandoth et al., 2013). Such mutations may allow pre-cancerous cells to breach the proliferation barrier posed by the DDR, thereby allowing the progression of pre-malignant lesions to malignant carcinomas. In addition, deregulation of DDR pathways also contributes to the development of genomic instability, a characteristic of human cancers that accelerates the genetic alterations which drive tumour development (Negrini et al., 2010, Hanahan and Weinberg, 2011). DDR mechanisms are also relevant to the effectiveness of standard cancer treatments, such as radio- and chemotherapy. These treatments rely on the induction of DNA damage, which is particularly cytotoxic for proliferating cells and hence, very effective in targeting highly proliferative cancer cells. Cancer cells can, however, resist the lethal effects of genotoxic cancer therapy by activating the DDR (Karnitz et al., 2005, Myers et al., 2009, Woods and Turchi, 2013), and since chemo- and radiotherapy generally lack selectivity towards cancer cells, the toxicity induced in normal tissues and the resulting side effects are limiting factors for the dose and duration of therapy. This is one of the reasons why these therapies, though effective, often fail to be curative. Also, tumours can develop resistance to radio- or chemotherapy allowing tumour recurrence following an initial response to therapy. Several studies have shown, that the development of resistance to different types of genotoxic therapy can be caused by deregulation and overexpression of different components of the DNA damage response (Bao et al., 2006, Oliver et al., 2010, Bobola et al., 2012).