Activation of p21 following DNA damage transcriptionally controlled by a telomeric shelterin protein TRF2 in a telomere‐length dependent fashion

Abstract

We report and unexpected finding ‐ TRF2 occupancy at the p21, as well as other promoters, depends on telomere‐length, even though the sites are as much as 62 Mb distal to the nearest telomere. And, p21 repression by TRF2 was telomere length‐dependent. Together our data are consistent with a model that involves partitioning of TRF2 between telomeres and interstitial sites, which influences gene regulation. DNA secondary structures called G‐quadruplexes were recently detected in‐vivo using antibodies. Further, it remains to be understood whether and how detected interstitial G‐quadruplexes function biologically. In support of the underlying mechanism of TRF2‐p21 regulation we find telomere repeat factor 2 (TRF2) associates with hundreds of potential interstitial G‐quadruplex sites, a significant number of which overlap with gene promoter regions. Detailed mutational and expression analysis of the cyclin‐dependent kinase CDKNIA (p21) promoter quadruplex site revealed TRF2 occupancy results in recruitment of the REST‐repressor protein complex and decreases p21 expression in response to drug induced DNA damage.Support or Funding InformationWellcome Trust ‐ Department of Biotechnology India Alliance and Council of Scientific and Industrial Research