Abstract
The human CST complex composed of CTC1, STN1, and TEN1 is critically involved in telomere maintenance and homeostasis. Specifically, CST terminates telomere extension by inhibiting telomerase access to the telomeric overhang and facilitates lagging strand fill in by recruiting DNA Polymerase alpha primase (Pol α-primase) to the telomeric C-strand. Here we reveal that CST has a dynamic intracellular localization that is cell cycle dependent. We report an increase in nuclear CST several hours after the initiation of DNA replication, followed by exit from the nucleus prior to mitosis. We identify amino acids of CTC1 involved in Pol α-primase binding and nuclear localization. We conclude, the CST complex does not contain a nuclear localization signal (NLS) and suggest that its nuclear localization is reliant on Pol α-primase. Hypomorphic mutations affecting CST nuclear import are associated with telomere syndromes and cancer, emphasizing the important role of this process in health.
Highlights
The human CST complex composed of CTC1, STN1, and TEN1 is critically involved in telomere maintenance and homeostasis
We report that CST nuclear import is mediated through an importin alpha-dependent mechanism even though there are no functional nuclear localization signals (NLS) found within the structures of CTC1, STN1, or TEN1
In addition to this guide sequence, a homology-directed repair template (HDR) was designed with an mCherry sequence flanked by 1000 nucleotides of the CTC1 gene on both sides (Fig. 1b, Supplementary Fig. 1)
Summary
The human CST complex composed of CTC1, STN1, and TEN1 is critically involved in telomere maintenance and homeostasis. CST terminates telomere extension by inhibiting telomerase access to the telomeric overhang and facilitates lagging strand fill in by recruiting DNA Polymerase alpha primase (Pol α-primase) to the telomeric C-strand. Aside from telomerase, two main protein complexes function in maintaining telomere homeostasis for mammalian cells: shelterin and CST6. Shelterin contains six subunits, termed TRF1, TRF2, TIN2, RAP1, POT1 and TPP1 It serves to cap telomeres, preventing the single-stranded telomeric overhangs from being recognized as DNA damage[7]. CST recruits DNA polymerase alpha primase (Pol α-primase) to the lagging telomeric strand to facilitate C-strand fill in, an essential process in finalizing doublestranded telomere replication[15]. Mislocalization could lead to telomeric homeostasis defects or replication stresses and could be causative for disease
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