Telomere-regulating genes and the telomere interactome in familial cancers

Abstract

Telomeres are repetitive sequence structures at the ends of linear chromosomes that consist of double-stranded DNA repeats followed by a short single-stranded DNA protrusion. Telomeres need to be replicated in each cell cycle and protected from DNA-processing enzymes, tasks that cells execute using specialized protein complexes such as telomerase (that includes TERT), which aids in telomere maintenance and replication, and the shelterin complex, which protects chromosome ends. These complexes are also able to interact with a variety of other proteins, referred to as the telomere interactome, to fulfill their biological functions and control signaling cascades originating from telomeres. Given their essential role in genomic maintenance and cell-cycle control, germline mutations in telomere-regulating proteins and their interacting partners have been found to underlie a variety of diseases and cancer-predisposition syndromes. These syndromes can be characterized by progressively shortening telomeres, in which carriers can present with organ failure due to stem cell senescence among other characteristics, or can also present with long or unprotected telomeres, providing an alternative route for cancer formation. This review summarizes the critical roles that telomere-regulating proteins play in cell-cycle control and cell fate and explores the current knowledge on different cancer-predisposing conditions that have been linked to germline defects in these proteins and their interacting partners.

Figure 1. Telomere-interacting proteins and their roles

a) The shelterin complex, composed of six proteins (left), and several of its associated proteins are depicted with the biological functions they play in the cell (right). For simplicity, TERF1 and TERF2 homodimers are drawn as single boxes. The alternative T- and D-loop telomere structures are shown. Tnk: Tankyrase, Ub: ubiquitination, P: phosphorylation, ADPr: ADP ribosylation. b) The members of the telomerase complex are shown bound to the G-strand overhang with a simplified structure for TERC, which provides the template for repeat addition.

Figure 2. Germline mutations in telomere-interacting proteins found in familial cancer-predisposition syndromes

The mutations depicted in panels a-c have been compiled from references (101) and (103). Protein structure has been taken from Ensembl release 75 (165) unless specified otherwise. a) Mutations in TERT. R83P: AA and MDS, V170M: AA and IPF, S368F: AA and IPF, H412Y: AA and AML, R631Q: DC and IPF, V694M: AA and IPF, P704S: DC, AA and IPF, Y846C: AA and DC, R865H: AA and IPF, R901W: DC and HHS, K902N: DC and AA, R979W: AA and DC, E116fs: AA and IPF, F1127L: DC and HHS. b) Mutations in TERC. The structure is taken from reference (103). A37G: DC and IPF, del52-55: DC and MDS, del 53-87: AA and IPF, U83G: AA and MDS, GC107-108AG: DC and AA, del 110-113: AA and MDS, C116U: AA and MDS, G143A: DC and AA. c) Mutations in TINF2. Structure taken from references (2) and (75). K280X: DC, HHS and Revesz syndrome, K280Rfs: DC and Revesz syndrome, R282S: DC and Revesz syndrome, R282C: DC and AA, R282H: DC, HHS and Revesz syndrome, P283S: DC and HHS, T284Hfs: DC and AA. d) Mutations in TCAB1. Protein structure taken from (166). Mutations taken from reference (34). e) Mutations in NOP10 were taken from reference (103). f) Mutations in NHP2 were taken from reference (103). g) Mutations in dyskerin, encoded by DKC1, were taken from references (103) and (127). P10L: DC and HHS, I38T: DC and HHS, T49M: DC and HHS, T66A: DC and HHS, T67I: DC and HHS, H68Q: DC and HHS, S121G: DC and HHS, R158W: DC and HHS, S304N: DC and HHS, K314R: DC and HHS, A353V: DC and HHS, A386T: DC and HHS. h) Mutations in RTEL1. Mutations have been taken from references (62), (104), (167) and (168). E591D: DC and HHS, R974X: DC and HHS, R986X: DC and HHS. i) Mutations in CTC1. Structure taken from reference (169) and mutations from (107). j) Mutations in POT1. Structure and mutations taken from references (141, 142).

Figure 2. Germline mutations in telomere-interacting proteins found in familial cancer-predisposition syndromes

The mutations depicted in panels a-c have been compiled from references (101) and (103). Protein structure has been taken from Ensembl release 75 (165) unless specified otherwise. a) Mutations in TERT. R83P: AA and MDS, V170M: AA and IPF, S368F: AA and IPF, H412Y: AA and AML, R631Q: DC and IPF, V694M: AA and IPF, P704S: DC, AA and IPF, Y846C: AA and DC, R865H: AA and IPF, R901W: DC and HHS, K902N: DC and AA, R979W: AA and DC, E116fs: AA and IPF, F1127L: DC and HHS. b) Mutations in TERC. The structure is taken from reference (103). A37G: DC and IPF, del52-55: DC and MDS, del 53-87: AA and IPF, U83G: AA and MDS, GC107-108AG: DC and AA, del 110-113: AA and MDS, C116U: AA and MDS, G143A: DC and AA. c) Mutations in TINF2. Structure taken from references (2) and (75). K280X: DC, HHS and Revesz syndrome, K280Rfs: DC and Revesz syndrome, R282S: DC and Revesz syndrome, R282C: DC and AA, R282H: DC, HHS and Revesz syndrome, P283S: DC and HHS, T284Hfs: DC and AA. d) Mutations in TCAB1. Protein structure taken from (166). Mutations taken from reference (34). e) Mutations in NOP10 were taken from reference (103). f) Mutations in NHP2 were taken from reference (103). g) Mutations in dyskerin, encoded by DKC1, were taken from references (103) and (127). P10L: DC and HHS, I38T: DC and HHS, T49M: DC and HHS, T66A: DC and HHS, T67I: DC and HHS, H68Q: DC and HHS, S121G: DC and HHS, R158W: DC and HHS, S304N: DC and HHS, K314R: DC and HHS, A353V: DC and HHS, A386T: DC and HHS. h) Mutations in RTEL1. Mutations have been taken from references (62), (104), (167) and (168). E591D: DC and HHS, R974X: DC and HHS, R986X: DC and HHS. i) Mutations in CTC1. Structure taken from reference (169) and mutations from (107). j) Mutations in POT1. Structure and mutations taken from references (141, 142).

Figure 2. Germline mutations in telomere-interacting proteins found in familial cancer-predisposition syndromes

The mutations depicted in panels a-c have been compiled from references (101) and (103). Protein structure has been taken from Ensembl release 75 (165) unless specified otherwise. a) Mutations in TERT. R83P: AA and MDS, V170M: AA and IPF, S368F: AA and IPF, H412Y: AA and AML, R631Q: DC and IPF, V694M: AA and IPF, P704S: DC, AA and IPF, Y846C: AA and DC, R865H: AA and IPF, R901W: DC and HHS, K902N: DC and AA, R979W: AA and DC, E116fs: AA and IPF, F1127L: DC and HHS. b) Mutations in TERC. The structure is taken from reference (103). A37G: DC and IPF, del52-55: DC and MDS, del 53-87: AA and IPF, U83G: AA and MDS, GC107-108AG: DC and AA, del 110-113: AA and MDS, C116U: AA and MDS, G143A: DC and AA. c) Mutations in TINF2. Structure taken from references (2) and (75). K280X: DC, HHS and Revesz syndrome, K280Rfs: DC and Revesz syndrome, R282S: DC and Revesz syndrome, R282C: DC and AA, R282H: DC, HHS and Revesz syndrome, P283S: DC and HHS, T284Hfs: DC and AA. d) Mutations in TCAB1. Protein structure taken from (166). Mutations taken from reference (34). e) Mutations in NOP10 were taken from reference (103). f) Mutations in NHP2 were taken from reference (103). g) Mutations in dyskerin, encoded by DKC1, were taken from references (103) and (127). P10L: DC and HHS, I38T: DC and HHS, T49M: DC and HHS, T66A: DC and HHS, T67I: DC and HHS, H68Q: DC and HHS, S121G: DC and HHS, R158W: DC and HHS, S304N: DC and HHS, K314R: DC and HHS, A353V: DC and HHS, A386T: DC and HHS. h) Mutations in RTEL1. Mutations have been taken from references (62), (104), (167) and (168). E591D: DC and HHS, R974X: DC and HHS, R986X: DC and HHS. i) Mutations in CTC1. Structure taken from reference (169) and mutations from (107). j) Mutations in POT1. Structure and mutations taken from references (141, 142).