Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Abstract

Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.

Pol α-primase dependent nuclear localization of the mammalian CST complex

“…This provides one possible mechanistic understanding to telomere syndromes caused by CST mutations. Since CTC1 loss results in unregulated telomere length, fragile telomeres, and increased genomic instability, the CST cancer-associated mutations in Supplementary Table 1 may contribute to oncogenesis 12 , 42 .…”

“…The CST complex is also critical in maintaining telomere homeostasis 11 . The human CST complex composed of CTC1, STN1, and TEN1 12 has dual roles in mediating telomere homeostasis. CST terminates the telomerase extension reaction 13 either by sequestering the telomeric overhang or via disruption of the TERT–TPP1 interaction 14 .…”

Non-canonical roles of canonical telomere binding proteins in cancers

“…It has been suggested that the upregulation of POT1 was necessary in restoring and maintaining 3′-overhang lengths in telomerase reactivated cancers, so as to prevent DNA damage response activation and to prolong survival and proliferation of cancer cells [ 258 ]. Numerous deleterious mutations in POT1 have been identified in different human cancers [ 259 ], many of which exist in the DNA-binding domain and disrupt POT1′s binding to 3′-overhangs, promoting telomere elongation and chromosomal instability. A handful of mutations occur in the TPP1-binding domain.…”

Revesz syndrome revisited

“…Hence, premature shortening of telomere repeats leads to premature cell senescence [62]. Regarding the variant molecular interactions of the mutant TIN2 protein with its natural ligands, the readers are referred to the respective literature [63][64][65]. It is still under debate whether the extent of telomere shortening is generally associated with the severity of symptoms [66,67].…”