Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Abstract

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

“…Although replication stress, defined as the deleterious effects of partially replicated DNA persisting in the nucleus, has been proposed as a mechanism for the observed DNA damage (Bartkova et al, 2006;Di Micco et al, 2006), our results would suggest that a significant part of the DNA damage and genetic instability observed in RAS-transformed cells originates from the oxidation products in the deoxynucleotide pool created by oncogenic RAS-induced ROS. It remains possible that oncogenic RAS-induced hyperproliferation (Di Micco et al, 2006) coupled with increased levels of oxidized guanine deoxynucleotides, leads to an even greater incorporation of these products into nuclear DNA during replication, in which they can contribute to replication stress.…”

“…Mouse models of OIS implicate DNA damage as a likely agent for triggering a proliferation arrest in vivo (Bartkova et al, 2006;Di Micco et al, 2006). Our study indicates that Figure 3 MTH1 expression does not show clear-cut effects on downstream oncogenic RAS signaling through the ERK pathway.…”

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…Replication stress or DNA damage is increased during o ncogenic transformation, which makes them more dependent upon DNA damage response pathways for cell survival (Bartkova et al, 2006;Bester et al, 2011;Vafa et al, 2002) . To cope with this stress many tumour cell lines elevate (Verlinden et al, 2007).…”

Replication stress and cancer: It takes two to tango

“…The mutation of MCM4 or MCM2 reduces the activity of the MCM complex, limiting the amount of available back-up origins, which results in increased RS, genomic instability and a cancer-prone phenotype [14][15][16]. In contrast, the overexpression of certain oncogenes (Myc, Ras…) has the opposite effect and increases the firing of origins of replication, leading to a depletion of the cellular pool of nucleotides (dNTPs) [17][18][19][20][21]. The reduced level of dNTPs slows down the progression of the forks and increases the chance of fork stalling per se.…”