CDK2-mediated phosphorylation of TRF1 S11 facilitates DNA damage repair by remodeling telomeric chromatin.

Telomeres, coated by the shelterin complex, prevent end-to-end fusions and aberrant DNA repair, yet how telomere-binding proteins coordinate chromatin remodeling during the DNA damage response remains unclear. Here we show that the telomeric protein TRF1 is phosphorylated at serine 11 (S11) in response to DNA double-strand breaks, a modification that enhances cellular resistance to DNA damage. We found that CDK2 directly mediates this phosphorylation, which triggers recruitment of the histone methyltransferase SETD5 to telomeric chromatin. SETD5-dependent deposition of H3 trimethylation at lysine 36 (H3K36me3) promotes local chromatin decompaction and enables subsequent recruitment of the phosphatase PPP4C to dephosphorylate γH2AX. Loss of TRF1 S11 phosphorylation results in persistent γH2AX foci, delayed DNA repair, and compromised telomere integrity. Our results define a CDK2-TRF1-SETD5-PPP4C signaling axis that orchestrates phosphorylation-dependent chromatin remodeling at telomeres to ensure genome maintenance during DNA damage stress.