Ionizing radiation (IR), widely used in diagnostic procedures and cancer therapy, induces complex clusters of damage in the genome that include DNA double‐strand breaks (DSB) and much higher levels of closely spaced oxidized bases and single strand‐breaks (SSB). While overt DSBs are primarily repaired via non‐homologous end joining (NHEJ), oxidized bases and SSBs are repaired via base excision repair (BER)/ SSB repair pathway. However, how these multiple repair pathways are co‐ordinated at IR‐induced damage clusters is poorly understood. Here we demonstrate temporal control of NHEJ vs. BER, co‐ordinated by RNA binding protein hnRNP‐U, which was recently implicated in regulating BER for enhancing the activities of NEIL1/NEIL2 glycosylases. We found Ku, a key NHEJ protein inhibits early BER proteins (NEILs, OGG1 & APE1) at the damage clusters, preventing repair of oxidized bases at close proximity. hnRNP‐U, also recruited at the repair site cannot overcome Ku inhibition initially due to its phosphorylated state (at S59 by DNA‐PK in response to IR). Subsequently, hnRNP‐U dephosphorylated after NHEJ completion relieves Ku inhibition and facilitates BER initiation. This differential ability of unmodified vs. S59‐P hnRNP‐U is due to its phosphorylation‐dependent decrease in affinity for the DNA glycosylases. These studies provide a molecular mechanism for sequential repair of IR‐induced DSBs followed by BER of proximal oxidized bases, where hnRNP‐U acts as a ‘molecular switch’. We propose that such hierarchical repair of IR‐induced damage is important in maintaining genomic fidelity.Grant Funding Source: Supported by USPHS grant R01 CA158910 and HMRI