Telomeric DNA damage is irreparable and causes persistent DNA damage response activation

By M. Fumagalli, F. Rossiello, Michela Clerici, S. Barozzi, Davide Cittaro, Jessica M. Kaplunov, G. Bucci, Miryana Dobreva, Valentina Matti, C. Beauséjour and 3 more. Nature Cell Biology, 2012

802 citations recorded by the source corpus.

The DNA-damage response (DDR) arrests cell-cycle progression until damage is removed. DNA-damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2f5fbabfc3ffede1bf470e39db9a9d16006b3dfa

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Citations in the corpus

Aging, Cellular Senescence, and Cancer (2012, positive): “Persistent DDR signaling is generally identified by the long-term presence of nuclear DNA damage foci that contain a variety of activated DDR proteins, including activated p53 (24, 29, 42, 43).”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, positive): “DNA damage results in increased deposition of γH2Ax and 53BP1 in chromatin that in turn activates a kinase cascade involving first ATM and ATR and then CHK1 and CHK2, eventually resulting in p53 activation (d’Adda di Fagagna, 2008; Fumagalli et al., 2012).”
Cellular senescence and its effector programs (2014, positive): “2011), has been associated with the maintenance of senescence primarily through p53 activation (Rodier et al. 2009; Fumagalli et al. 2012).”
Mechanisms and functions of cellular senescence. (2018, neutral): “, ANRIL) can dictate the recruitment that results in irreparable DNA damage (30).”
The hallmarks of aging. (2013, neutral): “Therefore, DNA damage at telomeres causes a persistent type of DNA damage that leads to deleterious cellular effects including senescence and/or apoptosis (Fumagalli et al., 2012; Hewitt et al., 2012).”