DNA damage-activated ABL-MyoD signaling contributes to DNA repair in skeletal myoblasts

Previous works have established a unique function of MyoD in the control of muscle gene expression during DNA damageresponse in myoblasts. Phosphorylation by DNA damage-activated ABL tyrosine kinase transiently inhibits MyoD-dependentactivation of transcription in response to genotoxic stress. We show here that ABL-MyoD signaling is also an essentialcomponent of the DNA repair machinery in myoblasts exposed to genotoxic stress. DNA damage promoted the recruitment ofMyoD to phosphorylated Nbs1 (pNbs1)-containing repair foci, and this effect was abrogated by either ABL knockdown or the ABLkinase inhibitor imatinib. Upon DNA damage, MyoD and pNbs1 were detected on the chromatin to MyoD target genes withoutactivating transcription. DNA damage-mediated tyrosine phosphorylation was required for MyoD recruitment to target genes, asthe ABL phosphorylation-resistant MyoD mutant (MyoD Y30F) failed to bind the chromatin following DNA damage, whileretaining the ability to activate transcription in response to differentiation signals. Moreover, MyoD Y30F exhibited an impairedability to promote repair in a heterologous system, as compared with MyoD wild type (WT). Consistently, MyoD-null satellite cells(SCs) displayed impaired DNA repair that was rescued by reintroduction of MyoD WT but not by MyoD Y30F. In addition,inhibition of ABL kinase prevented MyoD WT-mediated rescue of DNA repair in MyoD-null SCs. These results identify anunprecedented contribution of MyoD to DNA repair and suggest that ABL-MyoD signaling coordinates DNA repair andtranscription in myoblasts.