A role for heterochromatin protein 1 gamma at human telomeres

作者：Canudas Silvia; Houghtaling Benjamin R; Bhanot Monica; Sasa Ghadir; Savage Sharon A; Bertuch Alison A; Smith Susan^*

来源：Genes & Development, 2011, 25(17): 1807-1819.

DOI：10.1101/gad.17325211

• telomeres
• TIN2
• HP1
• dyskeratosis congenita

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 1 gamma (HP1 gamma), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1 gamma 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 HP1 gamma and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1 gamma in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.

• 出版日期2011-9-1