Mechanisms of oncogene-induced genomic instability

Abstract

Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation.

Autophagy role(s) in response to oncogenes and DNA replication stress

“…This may also explain why both DDR and autophagy activation appear to largely coincide in the early clinical lesions that we examined by immunohistochemistry, as these tissues, despite being collected from radio/chemotherapy-naive patients, were obviously obtained weeks, months or even years after the initial oncogenic event in vivo. Notably, our functional cell culture data are based on parallel analyses of several human cellular models and experiments with three different oncogenes commonly implicated in both pathogenesis and triggering of RS in a range of human cancers: H-Ras, c-Myc and cyclin E [45,[51][52][53]. While the precise kinetics of autophagy induction was, to some extent, oncogenedependent, the overall pattern of DDR signalling preceding an autophagy flux increase was shared by all models used.…”

Explore a novel function of human condensins in cellular senescence

“…Furthermore, mutation of SMC5 also leads to abnormal distribution of condensin along chromosomes with decreased condensin accumulation at pericentromeric regions and enrichment of condensin on chromosome arms in mouse embryonic stem cells (mESCs) [74]. There are complex chromatin reorganizations in senescent cells [75][76][77]. Recently, different models of SMC complex function have been presented [78][79][80].…”

Advances in research on the interaction between inflammation and cancer

“… 15 Therefore, various mutations in the cells accumulate in succession, resulting in oncogene activation and inactivation of tumour suppressor genes. 16 Sustained stimulation of chronic inflammation can cause immune tolerance in the body and mutant cells cannot be identified and cleared in time. 17 The combination of the above factors ultimately leads to the inevitable occurrence of tumours.…”