Post-GWAS functional analysis identifies CUX1 as a regulator of p16<sup>INK4a</sup> and cellular senescence.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37117763.
- Also identified by DOI 10.1038/s43587-022-00177-0 and PMC identifier 10154215.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 p14<sup>ARF</sup>, p15<sup>INK4b</sup> and p16<sup>INK4a</sup> 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 p16<sup>INK4a</sup> expression. Thus, our studies identify CUX1 as a regulator of p16<sup>INK4a</sup>-dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
Medical subject headings
- Atherosclerosis
- Cyclin-Dependent Kinase Inhibitor p16