title: DNA damage response: the emerging role of c-Abl as a regulatory switch?
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.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, I-00133 Rome, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Maiani
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Stefania
authors.initials: S
authors.lastname: Gonfloni
mesh_terms: D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016315:Proto-Oncogene Proteins c-abl