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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.

Transcription regulation of CDKN1A (p21/CIP1/WAF1) by TRF2 is epigenetically controlled through the REST repressor complex