Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes Page: 4 of 25
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the direct DNA binding proteins, TRF1 binds double stranded telomeric DNA and
is an important regulator of telomere length6. In contrast, TRF2, which also binds
double stranded telomeric DNA, is more important for telomere capping7-9 and t-
loop formation10. POT1 binds the single-stranded 3' overhang and is likely a
terminal regulator of telomere length and end protection.
TIN2 is an important telomere-associated protein because it binds both
TRF112 and TRF213,14,15 and indirectly interacts with POT1 via the intermediary
protein TPP1, also termed pTOP16, PIP17, and TINT18. TIN2 participates in the
regulation of telomere length through its interactions with TRF112 and TPP116,17,
18. In addition, TIN2 appears to be a critical component in forming telomere
complexes that function in end-protection3
The functions of the three telomeric DNA binding proteins (TRF1, TRF2
and POT1) are very likely coordinated. Perturbations to either TRF1 or TRF2, or
their associated proteins POT1, RAP1 or TIN2, influence both telomere length
and capping6,11-13,19-22. These observations suggest that TRF1, TRF2, POT1,
and TIN2 may function in the same pathway. Consistent with this idea, six
proteins co-purified in a large molecular weight complex14,15,23. This complex
may be the core molecular machinery that regulates mammalian telomeres. On
the other hand, gel filtration identified a TRF2-RAP1 complex that also contains
TIN2 and POT1 but not TRF114. Further, when TRF1 is removed from
telomeres, TIN2 and TPP1 remain at telomeres via increased association with
TRF218. And, although POT1 was shown to be associated with TRF119, POT1
and TRF2 also form a complex with telomeric DNA, and POT1 overexpression
protects against loss of telomeric single-stranded DNA caused by expression of a
dominant negative TRF2 (DN-TRF2)22. Thus, there may be distinct telomeric
complexes that participate in maintaining telomere length and capping.
It is not yet clear whether there is a single TIN2 complex, which always
contains TRF1, TRF2 and TPP1/POT1 and their interacting proteins, or whether
Kim et al.
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Kim, Sahn-Ho; Davalos, Albert R.; Heo, Seok-Jin; Rodier, Francis; Beausejour, Christian; Kaminker, Patrick et al. Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes, article, November 7, 2006; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc897420/m1/4/: accessed April 23, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.