Abstract:
:Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the human intervertebral disc, we exposed human nucleus pulposus (hNP) cells directly to the DNA damaging agent cisplatin. Cisplatin-treated hNP cells exhibited rapid phosphorylation of ATM and subsequent increased NF-κB activation, aggrecanolysis, decreased total proteoglycan production and increased expression of markers of senescence, including p21, γH2 AX and SA-ß-gal. Treating cisplatin-exposed hNP cells with an ATM-specific inhibitor negated these effects. In addition, genetic reduction of ATM reduced disc cellular senescence and matrix proteoglycan loss in the progeroid Ercc1-/∆ mouse model of accelerated ageing. These findings suggest that activation of ATM signalling under persistent genotoxic stress promotes disc cellular senescence and matrix homeostatic perturbation. Thus, the ATM signalling pathway represents a therapeutic target to delay the progression of age-associated spine pathologies.
journal_name
Aging Celljournal_title
Aging cellauthors
Han Y,Zhou CM,Shen H,Tan J,Dong Q,Zhang L,McGowan SJ,Zhao J,Sowa GA,Kang JD,Niedernhofer LJ,Robbins PD,Vo NNdoi
10.1111/acel.13162subject
Has Abstractpub_date
2020-07-01 00:00:00pages
e13162issue
7eissn
1474-9718issn
1474-9726journal_volume
19pub_type
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