In mammalian cells, changes in signaling networks and expressed proteins ensure the adequate detection and management of damaged macromolecules. Here, we review an emergent pathway of maintenance of homeostasis following genotoxic stress. The RNA-binding protein HuR associates with sirtuin (SIRT)1 mRNA and maintains constitutively elevated levels of SIRT1 protein, a deacetylase that elicits a prosurvival function. SIRT1 was recently shown to deacetylate the Nijmegen breakage syndrome (NBS1) protein, thereby rendering it phosphorylatable by ataxia telangiectasia mutated protein (ATM). A component of the MRN (MRE11-RAD50-NBS1) nuclease complex, NBS1 is crucial for sensing DNA damage and mounting a genotoxic response. This article covers the regulatory pathway of HuR-->SIRT1-->NBS1, through which post-transcriptional and post-translational effectors contribute to the maintenance of genomic integrity.