Abstract
Accumulation of senescent cells with age is an important driver of aging and age-related diseases. However, the mechanisms and signaling pathways that regulate senescence remain elusive. In this report, we performed post-genome-wide association studies (GWAS) functional studies on the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases and overall human lifespan. We demonstrate that transcription factor CUX1 (Cut-Like Homeobox 1) specifically binds to an atherosclerosis-associated functional single-nucleotide polymorphism (fSNP) (rs1537371) within the locus and regulates the CDKN2A/B-encoded proteins p14ARF, p15INK4b and p16INK4a and the antisense noncoding RNA in the CDK4 (INK4) locus (ANRIL) in endothelial cells (ECs). Endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced senescence via activation of p16INK4a expression. Thus, our studies identify CUX1 as a regulator of p16INK4a-dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
Highlights
Accumulation of senescent cells with age is an important driver of aging and age-related diseases
By coupling of regulatory element sequencing (Reel-seq) with flanking restriction-enhanced DNA pulldown–mass spectrometry (FREP–MS) and allele-imbalanced DNA pulldown–Western blot (AIDP–Wb), three techniques recently developed in our laboratory[28,29], we discovered that CUX1, a transcription factor known to play roles in cell migration, proliferation, differentiation, DNA damage repair and tumorigenesis[30], regulates both replicative and stress-induced senescence in human arterial
We found that the nine individuals with homozygous risk allele A/A expressed a significantly higher level of p16INK4a than the eight individuals carrying homozygous nonrisk allele C/C (P = 0.047, n = 17) as measured by quantitative PCR
Summary
Accumulation of senescent cells with age is an important driver of aging and age-related diseases. All these diseases are recognized as age-related pathologies in that their incidence markedly increases with age[7,8,9] Consistent with this observation, a genetic association of this locus with frailty and overall lifespan has been recently revealed[10,11,12]. The CDKN2A/B locus, spanning a 200-kb region, harbors three well-characterized tumor suppressor genes—p14ARF, p15INK4b, p16INK4a—and ANRIL Among these genes, p16INK4a has been implicated in the p16INK4a/RB pathway that leads to cellular senescence in a variety of cell types[23,24,25,26]. Relatively little is known about how p16INK4a expression is regulated in response to various stimuli that trigger senescence
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