A BRCA1-Dependent DNA Damage Response in the Regenerating Adult Peripheral Nerve Milieu
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It is not generally appreciated that DNA repair machinery has a critical role in the remodeling of neurons that adopt a regenerative phenotype. We identified that breast cancer 1 (BRCA1)-dependent DNA activity, previously well known to repair cancer cells, is active in adult peripheral neurons and Schwann cells during their injury and regeneration response. Temporary or partial loss of BRCA1 or blockade of its intraneuronal nuclear entry impaired outgrowth in neurons in vitro and impacted nerve regeneration and functional recovery in vivo. We found that distal axonal injury triggered a BRCA1-dependent DNA damage response (DDR) signal in neuronal soma. BRCA1 also supported an enabling transcriptional program of injured neurons and supporting Schwann cells. Our findings indicate that BRCA1 offers prominent functional roles in neurons and glial cells including key support for their physical and molecular integrity. Since BRCA1 mutations are common in humans, this function of BRCA1 in peripheral neurons and their glial partners warrants attention.
KeywordsBRCA1 Neuron DRG Schwann cells Peripheral nerve Regeneration
The work was supported by operating grants from the Canadian Institutes of Health Research (CIHR; FRN15686 and 184584) and the Canadian Diabetes Association (CDA; OG-3-12-3669) as well as support from the University of Alberta Hospital Foundation, the Department of Medicine and the Division of Neurology, Faculty of Medicine and Dentistry, University of Alberta. AK was supported by an Alberta Innovates Health Solutions (AI-HS) postdoctoral fellowship. The authors thank Dr. Jan Van Minnen for the gift of SCs used in this work. BRCA1-floxed mice breeder pairs were obtained from the National Cancer Institute (NCI) mouse repository.
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Conflict of Interest
The authors declare that they have no competing interests.
- 7.Keimpema E, Tortoriello G, Alpár A, Capsoni S, Arisi I, Calvigioni D, Hu SS, Cattaneo A et al (2013) Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci U S A 110(5):1935–1940CrossRefPubMedPubMedCentralGoogle Scholar