A persistent variant telomere sequence in a human pedigree

Angela M. Hinchie, Samantha L. Sanford, Kelly E. Loughridge, Rachel M. Sutton, Anishka H. Parikh, Agustin A. Gil Silva, Daniel I. Sullivan, Pattra Chun-On, Matthew R. Morrell, John F. McDyer, Patricia L. Opresko and Jonathan K. Alder ()
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Angela M. Hinchie: University of Pittsburgh
Samantha L. Sanford: University of Pittsburgh
Kelly E. Loughridge: University of Pittsburgh
Rachel M. Sutton: University of Pittsburgh
Anishka H. Parikh: University of Pittsburgh
Agustin A. Gil Silva: University of Pittsburgh
Daniel I. Sullivan: University of Pittsburgh
Pattra Chun-On: University of Pittsburgh
Matthew R. Morrell: University of Pittsburgh
John F. McDyer: University of Pittsburgh
Patricia L. Opresko: University of Pittsburgh
Jonathan K. Alder: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.

Date: 2024
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DOI: 10.1038/s41467-024-49072-9

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