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TRF2 regulates differential DNA damage response signaling from intermediate‐state and uncapped‐state telomeres
Author(s) -
Cesare Anthony J,
Hayashi Makoto T,
Karlseder Jan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.933.2
Subject(s) - telomere , chromatin , dna damage , microbiology and biotechnology , genome instability , dna , dna repair , chemistry , biology , genetics
There are three states of human telomere protection: a fully protected “closed‐state”, a DNA damage response (DDR) positive but fusion resistant “intermediate‐state” and a fusion competent “uncapped‐state”. We developed a system to induce intermediate‐or uncapped‐state telomeres in human primary and cancer cells through a graduated depletion of TRF2. We found intermediate‐state telomeres induce a localized ATM‐dependent DDR. However, TRF2 retained at the DDR‐positive chromosome end prevents RNF8 and RNF168 dependent fusions by inhibiting repair at a step between 53BP1 loading onto chromatin and telomeric 3′ overhang removal. Despite being γ‐H2AX positive, intermediate‐state telomeres fail to activate CHK2 and pass through G2 and M to induce p53‐dependent G1 arrest. Fusogenic uncapped‐state telomeres, on the contrary, trigger ATM‐CHK2 signaling analogous to double‐strand breaks. We conclude that TRF2 regulates a specialized chromatin environment by restricting DDR signaling and repair to maintain genomic stability in aged primary cells with spontaneous intermediate‐state telomeres. The NIH, the Human Frontier Science Program and the Japan Society for the Promotion of Science supported this work.