Abstract
Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.
Highlights
Genome instability is a defining hallmark of cancer [1] and is thought to promote tumorigenesis in pre-cancerous lesions, as well as karyotypic diversity during cancer progression [2,3,4]
These can be broadly classified into two categories: those that posit a requirement for genomic instability in the tumorigenesis process, and those that propose instability is merely a by-product of other genetic changes that occur during tumorigenesis
We propose that ATR inhibitors and MiDAS inhibitors could be an effective combinatorial strategy to trigger irreparable DNA replication stress in cells with activated oncogenes
Summary
Genome instability is a defining hallmark of cancer [1] and is thought to promote tumorigenesis in pre-cancerous lesions, as well as karyotypic diversity (and cellular heterogeneity) during cancer progression [2,3,4]. The ability of oncogenes to induce cell cycle entry and cell proliferation is well established Another consequence of oncogene activation, and the one of most relevance to the subject of this article, is the induction of chronic ‘DNA replication stress’. Given the prevalence of DNA replication stress in tumorigenesis, it is imperative to understand the defence mechanisms that cancer cells use to tolerate this stress This would afford us a potential opportunity to target a cancer cell-specific vulnerability. One such defence mechanism that was described recently in our laboratory is the activation of an atypical type of DNA synthesis that occurs in the early stages of mitosis [16]. We discuss how MiDAS serves as a salvage pathway to ensure completion of genome-wide replication and prevent pathological chromosome mis-segregation events
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