Sp1 phosphorylation by ATM downregulates BER and promotes cell elimination in response to persistent DNA damage.
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Date
2018-02-28ICR Author
Author
Fletcher, SC
Grou, CP
Legrand, AJ
Chen, X
Soderstrom, K
Poletto, M
Dianov, GL
Type
Journal Article
Metadata
Show full item recordAbstract
ATM (ataxia-telangiectasia mutated) is a central molecule for DNA quality control. Its activation by DNA damage promotes cell-cycle delay, which facilitates DNA repair prior to replication. On the other hand, persistent DNA damage has been implicated in ATM-dependent cell death via apoptosis; however, the mechanisms underlying this process remain elusive. Here we find that, in response to persistent DNA strand breaks, ATM phosphorylates transcription factor Sp1 and initiates its degradation. We show that Sp1 controls expression of the key base excision repair gene XRCC1, essential for DNA strand break repair. Therefore, degradation of Sp1 leads to a vicious cycle that involves suppression of DNA repair and further aggravation of the load of DNA damage. This activates transcription of pro-apoptotic genes and renders cells susceptible to elimination via both apoptosis and natural killer cells. These findings constitute a previously unrecognized 'gatekeeper' function of ATM as a detector of cells with persistent DNA damage.
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Subject
Killer Cells, Natural
Cells, Cultured
Humans
DNA Damage
Serine
Apoptosis
DNA Repair
Down-Regulation
Phosphorylation
Male
Sp1 Transcription Factor
Ataxia Telangiectasia Mutated Proteins
X-ray Repair Cross Complementing Protein 1
Research team
Cell Death and Immunity
Language
eng
Date accepted
2017-12-19
License start date
2018-02
Citation
Nucleic acids research, 2018, 46 (4), pp. 1834 - 1846
Publisher
OXFORD UNIV PRESS