Abstract
Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of p16INK4a promoter is associated with DNA damage caused by interference between transcription and replication processes. Inhibition of replication or transcription significantly reduces the DNA damage and CpGs methylation of the p16INK4a promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of p16INK4a and ultimately removes this barrier to oncogene-induced senescence.
Highlights
Cancer progression is characterized by the accumulation of genetic mutations and epigenetic alterations, which disrupt regulatory control mechanisms and profoundly affect cellular proliferation potential, growth signaling, neovascularization, and apoptosis [1,2,3].In normal cells, progression into cell cycle is tightly regulated by a set of proteins that control the cell cycle checkpoints [4,5]
We have found that DNA damage and repair modify local DNA methylation profiles
The observed changes to the cell cycle were modest, as approximately only 10–15% of the cells were synchronized followed by 2 h of serum starvation, these differences were significant and reproducible as demonstrated by p values below 0.05 (Figure 2A)
Summary
Cancer progression is characterized by the accumulation of genetic mutations and epigenetic alterations, which disrupt regulatory control mechanisms and profoundly affect cellular proliferation potential, growth signaling, neovascularization, and apoptosis [1,2,3]. Progression into cell cycle is tightly regulated by a set of proteins that control the cell cycle checkpoints [4,5] These checkpoints are often deregulated in cancer secondary to the silencing of various tumor suppressor genes [5,6]. In a precise time frame following DNA repair, transcription further remodels the methylation landscape, generating polymorphic methylation profiles that are transmitted to daughter cells. This association between DNA damage, repair, and methylation has been validated in several biological systems and cells [8,9,10]. AThlderiectho,pSotsLidoeuis, (SiMgmOa,-UASlAdr)icwha,sStadLdouedis,toMcOe,llUcSuAltu) wreams aedddiuemd tfoocre3l0l cmulitnu,rbeemfoerdeiuhamrvfoesrt3in0gmtihne,mbeifnoraenhaaprvpersotpinrigate thevmoluinmaeninapoprdroeprrtioatreeavcohluthmeefiinnaolrcdoenrcteonrtreaatcihonthoef f2i5naμlMco.ncentration of 25 μM
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