A role for heterochromatin protein 1γ at human telomeres

S Canudas, BR Houghtaling, M Bhanot… - Genes & …, 2011 - genesdev.cshlp.org
S Canudas, BR Houghtaling, M Bhanot, G Sasa, SA Savage, AA Bertuch, S Smith
Genes & development, 2011genesdev.cshlp.org
Human telomere function is mediated by shelterin, a six-subunit complex that is required for
telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has
binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner,
heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif,
PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S
phase, where it is required to establish/maintain cohesion. We further demonstrate that the …
Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1γ and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1γ in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.
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