SURF2 is a regulatory protein that functions as an MDM2 antagonist in the nucleolar stress response pathway 1. Upon ribosome assembly defects, free 5S ribonucleoprotein (RNP) particles accumulate and normally sequester MDM2 to promote p53 stabilization; however, SURF2 buffers these free 5S RNP particles and modulates their activity, thereby attenuating the p53-dependent stress response 1. This buffering mechanism allows cancer cells to resist nucleolar stress induced by chemotherapies, as SURF2 depletion increases cellular sensitivity to such stress while overexpression promotes resistance 1. SURF2 is located on chromosome 9 as part of the highly conserved Surfeit gene cluster, organized as a tightly packed locus of six unrelated housekeeping genes 2. The gene is regulated by a bidirectional promoter shared with SURF1, containing conserved factor-binding sites including YY1 binding elements 3. Clinically, SURF2 is overexpressed across multiple cancer types and serves as an independent prognostic marker for adrenocortical cancer 1. Recent evidence suggests SURF2 may also be relevant to Alzheimer's disease pathogenesis, where increased expression is associated with decreased disease risk 4.