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Abstract
ABSTRACTTIN2 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 clustered regularly interspaced short palindromic repeat (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.
Highlights
TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1
Prior studies have focused on the shorter isoform of TIN2; our data reveal differences in the interactions of TIN2S and TIN2L with TRF1 and TRF2, suggesting that the composition of the shelterin complex and the interactions within may be even more complex than previously thought [7, 43, 45, 49]
Previous studies have indicated that dyskeratosis congenita (DC)-associated mutations do not uniformly impact TIN2S interaction with TRF1, TRF2, and TPP1 [22, 23], the impact of the most common DC-associated mutation on TIN2L’s ability to bind to both TRF1 and TRF2 leaves open the possibility that the mcb.asm.org 10
Summary
TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Telomere lengths are unchanged in cell lines in which TIN2L expression has been eliminated by clustered regularly interspaced short palindromic repeat (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. The protein interaction domains, the region where all DC-causing mutations cluster (DC), the position of R282 (*), and the putative TBM, all of which are present in both the TIN2L and TIN2S isoforms, and the C-terminal domain unique to TIN2L (TIN2L CTD) are indicated. Whether the C-terminal TIN2L extension influences TIN2’s interaction with its shelterin binding partners has not been determcb.asm.org 2
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