Cell. 2015 Jun 18;161(7):1592-605. doi:10.1016/j.cell.2015.05.032

Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH.

Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes.

Double-strand breaks (DSBs) caused by the topoisomerase inhibitor etoposide induces early-response genes in neurons. The radiomimetic drugs neocarzinostatin and bleomycin, and the PARP inhibitor Olaparib did cause induction. Inhibition of DSB signalling with the ATM (ataxia telangiectasia mutated) inhibitor KU55933 did not suppress the induction. Knockdown of topoisomerase IIβ suppressed the induction. CRISPR-Cas9 DNA cleavage micmicked and rescued the induction. Topoisomerase IIβ and the breaks are enriched near CTCF binding sites. Tyrosyl DNA phosphodiesterase 2 (TDP2) is also enriched at the promoter of immediate early genes.