DNA Replication Stress as a Hallmark of Cancer

Abstract

Human cancers share properties referred to as hallmarks, among which sustained proliferation, escape from apoptosis, and genomic instability are the most pervasive. The sustained proliferation hallmark can be explained by mutations in oncogenes and tumor suppressors that regulate cell growth, whereas the escape from apoptosis hallmark can be explained by mutations in the TP53, ATM, or MDM2 genes. A model to explain the presence of the three hallmarks listed above, as well as the patterns of genomic instability observed in human cancers, proposes that the genes driving cell proliferation induce DNA replication stress, which, in turn, generates genomic instability and selects for escape from apoptosis. Here, we review the data that support this model, as well as the mechanisms by which oncogenes induce replication stress. Further, we argue that DNA replication stress should be considered as a hallmark of cancer because it likely drives cancer development and is very prevalent.

Genome Stability Requires p53

“…Oncogenes, which cause hyperproliferative signals, including DNA replication stress that can lead to DNA damage, activate p53 (Hills and Diffley 2014;Macheret and Halazonetis 2015). For example, increased expression or aberrant expression of the Myc oncogene activates p53, which results in apoptosis, protecting the cell from hyperproliferation.…”

ATM Mutations in Cancer: Therapeutic Implications

“…Defective DNA repair is a hallmark of cancer and results in genomic instability and accumulation of other genetic abnormalities (1,2). Hereditary mutations of genes involved in DNA repair, such as ataxia telangiectasia mutated (ATM), breast cancer (BRCA) 1 or 2, and TP53, result in markedly increased susceptibility to a variety of cancers.…”

Regional signals in the planarian body guide stem cell fate in the presence of DNA instability

“…DNA replication stress is one of the earliest manifestations of cellular transformation (Bartkova et al, 2006;Halazonetis et al, 2008;Macheret and Halazonetis, 2015). Furthermore, DNA damage response, particularly the repair of DNA double-strand breaks (DSBs), serves as an early anti-cancer barrier (Bartkova et al, 2006).…”