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Biochem Pharmacol. 2011 Nov 15;82(10):1269-76. doi: 10.1016/j.bcp.2011.07.001. Epub 2011 Jul 7.

DNA damage response: the emerging role of c-Abl as a regulatory switch?

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1
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, I-00133 Rome, Italy.

Abstract

A complex regulatory network of signaling pathways safeguards genome integrity following DNA damage. When double strand breaks occur several enzymes and mediators are recruited to the sites of lesion to release a network of DNA repair processes referred to as DNA damage response (DDR). c-Abl interacts in the nucleus with several proteins implicated in distinct aspects of DNA repair. This suggests that c-Abl may be involved in the regulation of double strand break repair. The involvement of c-Abl in DNA repair mechanisms came into the spotlight in female germ cells under genotoxic stress. Recent findings have implicated c-Abl in a cisplatin-induced signaling pathway eliciting death of immature oocytes. Pharmacological inhibition of c-Abl by Imatinib (STI571) protects the ovarian reserve from the toxic effect of cisplatin. This implies that the extent of c-Abl catalytic outcomes may tip the balance between survival (likely through DNA repair) and activation of a death response. Many observations indicate that timely ubiquitin-modifications and signal decoding are implicated in regulating DNA repair. Here, we discuss some connections between phosphorylation- and ubiquitin-mediated signaling at the damaged sites. We speculate about multiple interactions that may occur between c-Abl (and 'sensor' kinases) with ubiquitin-related proteins involved in DDR. Additional work is required to understand the complexity of the physiological outcomes of c-Abl in DDR. However, a fine-tuning of nuclear outcomes, through pharmacological inhibition of c-Abl, may provide novel paradigms for DDR and, potentially, therapeutic strategies for cancer treatment.

PMID:
21763684
DOI:
10.1016/j.bcp.2011.07.001
[Indexed for MEDLINE]

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