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N-terminal domain of TRF-interacting nuclear factor 2; shelterin complex protein of telomeres TIN2 is one of the six proteins of shelterin complex, which acts to protect telomeres from DNA damage repair machinery. TIN2 binds directly to TRF1 and TRF2 and stabilizes TRF2 complex-telomere binding by tethering it to the TRF1 complex. TIN2 binding to TRF2 is primarily via the TRF binding motif (TBM) region and the N-terminus, while the far C-terminal region has lower affinity. The TIN2 TBM, but not the N-terminal region, is involved in TIN2 binding to TRF1. Truncation of the TIN2 N-terminus in mouse results in telomere elongation, suggesting a negative regulatory function of this region. Three shelterin components (TRF1, TRF2, POT1) bind DNA and 3 components (TIN2, RAP1, TPP1) are recruited by these DNA binding factors. TRF1 activity at telomeres is regulated in part by selective ubiquitination and degradation. Ubiquitination of TRF1 is mediated by Fbx4, which binds TRF1 in the TRFH domain, via a small GTPase module. When bound to telomeres, TIN2 acts to protect TRF1 from SCF-Fbx4 mediated ubiquitination. F-box proteins act in substrate recognition as part of Skp1-Cul1-Rbx1-F- box (SCF) protein complexes. Tankyrase-mediated ADP-ribosylation releases TRF1 from telomeres, rendering them susceptible to ubiquitination and degradation, promoting telomere elongation. TIN2 also binds PIP1, which recruits POT1 to telomeres. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",