DNA damage signalling guards against activated oncogenes and tumour progression

Abstract

DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture and animal models as well as analyses of clinical specimens show that activation of numerous oncogenes and loss of some tumour suppressors result in DNA replication stress and DNA damage that alarm the cellular DDR machinery, a multifaceted response orchestrated by the ATR-Chk1 and ATM-Chk2 kinase signalling pathways. Such activation of the DDR network leads to cellular senescence or death of oncogene-transformed cells, resulting in delay or prevention of tumorigenesis. At the same time, the ongoing chronic DDR activation creates selective pressure that eventually favours outgrowth of malignant clones with genetic or epigenetic defects in the genome maintenance machinery, such as aberrations in the ATMChk2-p53 cascade and other DDR components. Furthermore, the executive DDR machinery is shared by at least two anticancer barriers, as both the oncogene-induced DNA replication stress and telomere shortening impact the cell fate decisions through convergence on DNA damage signalling. In this study, we highlight recent advances in this rapidly evolving area of cancer research, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

“…A senescence-like phenotype of doxorubicin-treated fibroblasts in G2 To investigate the cellular response to genotoxic stress at the level of APC/C regulation we used primary fibroblasts, as most transformed cell lines have acquired genetic alterations in DNA damage checkpoint pathways (Bartek et al, 2007). In particular, we wanted to address whether the silent APC/C of S/ G2 cells could be activated in response to DNA damage.…”

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

“…Apart from aging, several different stimuli can trigger senescence in normal human cells. For instance, oncogene activation in normal cells induces a permanent proliferative arrest termed oncogene-induced senescence, which functions as a barrier to cell transformation (Braig and Schmitt, 2006;Bartek et al, 2007). Although cancer cells bypass both replicative and oncogene-induced senescence, the genetic program of senescence in these cells seems to be repressed, but not lost, in such a way that it can be reactivated by expression of critical regulators.…”

Dissecting Molecular Events in Thyroid Neoplasia Provides Evidence for Distinct Evolution of Follicular Thyroid Adenoma and Carcinoma

“…It is proposed that the DDR machinery acts as an anticancer barrier, protecting cells against the progression of tumors from their early stages into malignant invasive lesions. 19 In a seminal paper, Bartkova et al 4 demonstrated that several human tumors (but not normal tissue) express markers of an activated DDR, including ATM, Chk2, phosphorylated H2AX, and p53, in their very early premalignant stages. Tort et al 30 recently showed in human colon adenomas that high-risk grade III adenomas show multiple markers of DDR activation, whereas low-grade adenomas (grades I and II) lack detectable markers of activated DDR.…”

“…Taken together, we observed the constitutive activation of DNA damage checkpoints exclusively in FTC with a combined overexpression of S-phase promoting cell-cycle kinases cyclin E, E2F1, and Rb1. Because it is hypothesized that among the early lesions of the same tissue the DDR barrier becomes only alarmed in those tumors that bear a higher risk of malignant progression, 4,19 these data could suggest that FAs evolve distinctly from FTCs.…”

“…19 Thus, it is proposed, that the DDR machinery acts as an anticancer barrier, protecting cells against the progression of tumors from their early stages into malignant invasive lesions. 4,19 This principle has been demonstrated for a number of human malignant neoplasms. Therefore, we asked whether similar changes are also present in follicular thyroid tumors and would suggest sequential evolution of FA to FTC.…”