RGD Reference Report - Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins.

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Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins.
Authors:	Lovric, J Mano, M Zentilin, L Eulalio, A Zacchigna, S Giacca, M
Citation:	Lovric J, etal., Mol Ther. 2012 Nov;20(11):2087-97. doi: 10.1038/mt.2012.144. Epub 2012 Jul 31.
RGD ID:	8693392
Pubmed:	PMID:22850678 (View Abstract at PubMed)
PMCID:	PMC3493462 (View Article at PubMed Central)
DOI:	DOI:10.1038/mt.2012.144 (Journal Full-text)
Gene therapy vectors based on the adeno-associated virus (AAV) are extremely efficient for gene transfer into post-mitotic cells of heart, muscle, brain, and retina. The reason for their exquisite tropism for these cells has long remained elusive. Here, we show that upon terminal differentiation, cardiac and skeletal myocytes downregulate proteins of the DNA damage response (DDR) and that this markedly induces permissivity to AAV transduction. We observed that expression of members of the MRN complex (Mre11, Rad50, Nbs1), which bind the incoming AAV genomes, faded in cardiomyocytes at ~2 weeks after birth, as well as upon myoblast differentiation in vitro; in both cases, withdrawal of the cells from the cell cycle coincided with increased AAV permissivity. Treatment of proliferating cells with short-interfering RNAs (siRNAs) against the MRN proteins, or with microRNA-24, which is normally upregulated upon terminal differentiation and negatively controls the Nbs1 levels, significantly increased permissivity to AAV transduction. Consistently, delivery of these small RNAs to the juvenile liver concomitant with AAV markedly improved in vivo hepatocyte transduction. Collectively, these findings support the conclusion that cellular DDR proteins inhibit AAV transduction and that terminal cell differentiation relieves this restriction.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Mre11	Rat	host-mediated suppression of symbiont invasion		IMP			RGD
Nbn	Rat	host-mediated suppression of symbiont invasion		IMP			RGD
Rad50	Rat	host-mediated suppression of symbiont invasion		IMP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Mre11 (MRE11 homolog, double strand break repair nuclease)

Nbn (nibrin)

Rad50 (RAD50 double strand break repair protein)

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Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins.