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SMCHD 1 promotes ATM ‐dependent DNA damage signaling and repair of uncapped telomeres
Author(s) -
Vančevska Aleksandra,
Ahmed Wareed,
Pfeiffer Verena,
Feretzaki Marianna,
Boulton Simon J,
Lingner Joachim
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102668
Subject(s) - biology , telomere , microbiology and biotechnology , dna damage , dna , genetics
Structural maintenance of chromosomes flexible hinge domain‐containing protein 1 ( SMCHD 1) has been implicated in X‐chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD 1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD 1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD 1 is required for DNA damage signaling and non‐homologous end joining ( NHEJ ) at unprotected telomeres. Co‐depletion of SMCHD 1 and the shelterin subunit TRF 2 reduced telomeric 3′‐overhang removal in time‐course experiments, as well as the number of chromosome end fusions. SMCHD 1‐deficient cells displayed reduced ATM S1981 phosphorylation and diminished formation of γH2 AX foci and of 53 BP 1‐containing telomere dysfunction‐induced foci ( TIF s), indicating defects in DNA damage checkpoint signaling. Removal of TPP 1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF 2‐depleted SMCHD 1 knockout cells. Together, these data indicate that SMCHD 1 depletion reduces telomere fusions in TRF 2‐depleted cells due to defects in ATM ‐dependent checkpoint signaling and that SMCHD 1 mediates DNA damage response activation upstream of ATM phosphorylation at uncapped telomeres.