Telomere length homeostasis, dictating cellular proliferative potential, is crucial for proper cellular function. In addition to the well-known telomere shortening during cell division and lengthening by activation of telomerase or an alternative lengthening of telomeres (ALT) mechanism, telomere length is also subject to regulated rapid deletion events referred to as telomere trimming1. This trimming process involves excision of telomeric structures called T-loops, which requires homologous recombination proteins XRCC3 and NBS12,3. Recent studies showed that the balance between telomere trimming and lengthening determines telomere length in germline and stem cells, suggesting that telomere trimming should be under stringent control4,5. However, the regulation of telomere trimming remains largely unknown.

We first generated a construct of TZAP that included Znf9-11 (residues 516-605). Using FP (fluorescence polarization) assay, we showed that the Znf9-11 construct displayed a relatively low binding affinity (> 30 μM) to a double-stranded oligonucleotide containing TTAGGG sequence (referred to as TTAGGG probe) (Figure 1B and Supplementary information, Table S1). We then noticed that there is an evolutionarily conserved and highly basic region (residues 606-620) located immediately C-terminal to Znf11 (Supplementary information, Figure S1). The construct containing Znf9-11 and the conserved C-terminal region (residues 516-620, referred to as Znf9-11-C) bound the TTAGGG dsDNA probe with a KD of about 0.18 μM in 150 mM NaCl solution, indicating a critical role of the C-terminal region in telomeric DNA binding (Figure 1B).

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