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The C-terminal extension unique to the long isoform of the shelterin component TIN2 enhances its interaction with TRF2 in a phosphorylation- and dyskeratosis congenita-cluster-dependent fashion

Nelson, Nya D., Dodson, Lois M., Escudero-Monreal, Laura, Sukumar, Ann T., Williams, Christopher L., Mihalek, Ivana, Baldan, Alessandro, Baird, Duncan M. ORCID: https://orcid.org/0000-0001-8408-5467 and Bertuch, Alison A. 2018. The C-terminal extension unique to the long isoform of the shelterin component TIN2 enhances its interaction with TRF2 in a phosphorylation- and dyskeratosis congenita-cluster-dependent fashion. Molecular and Cellular Biology 38 (12) , e00025-18. 10.1128/MCB.00025-18

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Abstract

TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Mutations in TINF2, which encodes TIN2, that are found in dyskeratosis congenita (DC) result in very short telomeres and cluster in a region shared by the two TIN2 isoforms, TIN2S (short) and TIN2L (long). Here we show that TIN2L, but not TIN2S, is phosphorylated. TRF2 interacts more with TIN2L than TIN2S, and both the DC-cluster and phosphorylation promote this enhanced interaction. The binding of TIN2L, but not TIN2S, is affected by TRF2-F120, which is also required for TRF2's interaction with end processing factors such as Apollo. Conversely, TRF1 interacts more with TIN2S than with TIN2L. A DC-associated mutation further reduces TIN2L-TRF1, but not TIN2S-TRF1, interaction. Cells overexpressing TIN2L or phosphomimetic-TIN2L are permissive to telomere elongation, whereas cells overexpressing TIN2S or phosphodead-TIN2L are not. Telomere lengths are unchanged in cell lines in which TIN2L expression has been eliminated by CRISPR/Cas9-mediated mutation. These results indicate that TIN2 isoforms are biochemically and functionally distinguishable, and that shelterin composition could be fundamentally altered in patients with TINF2 mutations.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Society for Microbiology
ISSN: 0270-7306
Date of First Compliant Deposit: 20 April 2018
Date of Acceptance: 26 March 2018
Last Modified: 12 Nov 2023 09:21
URI: https://orca.cardiff.ac.uk/id/eprint/110828

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