Double strand breaks are one of the most lethal forms of DNA lesions that, if left unrepaired can lead to genomic instability, cellular transformation, and cell death. However, cells have two main machineries namely error prone Non homologous end joining repair (NHEJ) or an accurate homology dependent repair to repair the double strand breaks. NHEJ is the preferred mechanism for DNA repair and basically consists of two forms: Canonical (C-NHEJ) and Alternative (A-NHEJ) NHEJ. Our study examined the cellular repair outcome when NHEJ is blocked by targeting two key DNA repair proteins: XRCC4 and MRE-11. We developed an extrachromosomal NHEJ fluorescent reporter assay that uses Transcription activator-like effector nucleases (TALEN) to introduce double strand breaks and detect the NHEJ editing by the presence of GFP fluorescence. We demonstrated the presence of NHEJ editing in the XRCC4(-/-) cells treated with Mirin (a pharmacological inhibitor of MRE-11), albeit with a ~52% efficiency of the normal cells. The transcriptional profiles of the Mirin treated HeLa XRCC4(-/-) cells had 307 uniquely differentially expressed genes that was far greater than HeLa XRCC4(-/-) sample (83 genes) and Mirin treated HeLa cells (30 genes). Pathway analysis unique to the XRCC4(-/-) +Mirin group included differential expression of p53 downstream pathways, and metabolic pathways indicating cell adaptation for energy regulation and stress response. In conclusion, our study showed that the double strand DNA repair can be sustained even in absence of key DNA repair proteins XRCC4 and MRE-11.