Abstract
We observed extra-telomeric binding of the telomere repeat binding factor TRF2 within the promoter of the cyclin-dependent kinase CDKNIA (p21/CIP1/WAF1). This result in TRF2 induced transcription repression of p21. Interestingly, p21 repression was through engagement of the REST-coREST-LSD1-repressor complex and altered histone marks at the p21 promoter in a TRF2-dependent fashion. Furthermore, mutational analysis shows p21 repression requires interaction of TRF2 with a p21 promoter G-quadruplex. Physiologically, TRF2-mediated p21 repression attenuated drug-induced activation of cellular DNA damage response by evading G2/M arrest in cancer cells. Together these reveal for the first time role of TRF2 in REST- repressor complex mediated transcription repression.
Highlights
Specialized ends of linear human chromosomes – called telomeres, comprising the repeated DNA motif TTAGGG - are involved in maintaining genome integrity by protecting the chromosomal ends from degradation and end to end fusion[1,2,3,4]
While full-length Telomere repeat factor 2 (TRF2) suppressed p21 promoter activity, TRF2 mutants lacking basic and/or myb DNA binding domains (TRF2-deletion of basic (delB), TRF2-delM and TRF2-delB-delM)[22] did not show any repression in p21 promoter activity (Fig. 1C). Consistent with this TRF2 overexpression resulted in low p21 protein levels (Fig. 1D, Supplementary Figure S1J), while TRF2 silencing resulted in increase in p21 protein (Fig. 1E, Supplementary Figure S1K) and mRNA (Fig. 1F) expression in HT1080 cells
These results demonstrate that TRF2 has extra-telomeric occupancy at p21 promoter and can regulate p21 expression
Summary
Specialized ends of linear human chromosomes – called telomeres, comprising the repeated DNA motif TTAGGG - are involved in maintaining genome integrity by protecting the chromosomal ends from degradation and end to end fusion[1,2,3,4]. Much is known about TRF2 functions in chromosome-end protection, it was only recently that genome-wide TRF2 binding was detected outside the telomeres of which many sites were interstitial telomeric-repeat sequences (ITS)[12, 13]. Karlseder et al observed increased expression of TRF2 delayed senescence in pre-senescent primary cultures[21]. It was not clear whether TRF2 directly influenced p21 expression. In light of the recent findings related to extra-telomeric occupancy[12, 13] and functions of TRF214, 15 we sought to investigate if TRF2 had any direct role in p21 regulation. This was supported by occupancy of TRF2 at the p21 proximal promoter and reporter assays supporting direct transcriptional role of TRF2. Together with other observations TRF2-mediated p21 regulation was found to influence how cancer cells manage DNA damage upon treatment with DNA-damaging drugs implicating its relevance in drug-resistant settings
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
