The Telomere-Associated TZAP Protein Limits Telomere Length

Regulation of telomere length is essential for chromosomal stability, and short telomeres are associated with cancer and premature aging. Telomeres associate with many proteins, but the interactions have not been fully characterized. Li and colleagues found that the kruppel-like zinc finger protein ZBTB48 was associated with telomeres, and ultimately renamed it telomeric zinc finger–associated protein (TZAP). TZAP exclusively and specifically interacted with telomeres and bound directly to TTAAGGG telomeric repeats in both telomerase-positive and telomerase-negative cells. TZAP bound preferentially to long telomeres with reduced concentrations of the shelterin complex, which is enriched at short telomeres. Further, TZAP competed with the shelterin complex component telomere repeat binding factor TRF2 for telomere binding, and elevated TRF2 expression reduced TZAP binding to telomeres, providing a mechanism by which TZAP might preferentially associate with long telomeres. Overexpression of TZAP resulted in a reduction in telomere length via telomere trimming, a process in which T-loops, a secondary telomeric structure, are deleted, leading to the accumulation of extrachromosomal telomeric DNA (ECT-DNA). These findings indicate a role for TZAP in limiting telomere length. Consistent with these results, CRISPR/Cas9-mediated deletion of TZAP resulted in telomere elongation and a reduction in ECT-DNA. Taken together, these data provide a mechanism by which TZAP may preferentially bind to long telomeres to promote telomere trimming and limit telomere length, thereby preventing the accumulation of abnormally long telomeres.

Li JS, Miralles Fusté J, Simavorian T, Bartocci C, Tsai J, Karlseder J, et al. TZAP: A telomere-associated protein involved in telomere length control. Science 2017;355:638–41.

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