Abstract
Genomic instability plays a key role in driving cancer development. It is already found in precancerous lesions and allows the acquisition of additional cancerous features. A major source of genomic instability in early stages of tumorigenesis is DNA replication stress. Normally, origin licensing and activation, as well as replication fork progression, are tightly regulated to allow faithful duplication of the genome. Aberrant origin usage and/or perturbed replication fork progression leads to DNA damage and genomic instability. Oncogene activation is an endogenous source of replication stress, disrupting replication regulation and inducing DNA damage. Oncogene-induced replication stress and its role in cancer development have been studied comprehensively, however its molecular basis is still unclear. Here, we review the current understanding of replication regulation, its potential disruption and how oncogenes perturb the replication and induce DNA damage leading to genomic instability in cancer.
Highlights
Genomic instability, found in most cancers, is considered one of the hallmark characteristics of cancer cells
Oncogene-induced replication stress plays a major role in early cancer development
Several forms of replication perturbation leading to genomic instability have been reported following oncogene activation
Summary
Found in most cancers, is considered one of the hallmark characteristics of cancer cells. Several factors have been suggested to underlie genomic instability found in cancer cells such as telomere attrition [6], oxidative stress [7] and defective DNA damage repair [8] These factors mainly contribute to genomic instability apparent in advanced stages of cancer development. Oncogene activation was found to induce endogenous replication stress leading to genomic instability and DNA damage response (DDR) in early cancer stages [13,14] This DDR activation could lead to proliferation arrest either in the form of senescence or apoptosis, forming a tumorigenic barrier [13,14]. Several mechanisms were suggested to underlie oncogene-induced replication stress including: cell cycle regulation enforcing proliferation, deregulating origin licensing and activation as well as endangering faithful replication fork progression and genome duplication. We will discuss suggested mechanisms underlying oncogene-induced replication stress and how such replication stress may induce genomic instability in cancer
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