DCLRE1B (DNA cross-link repair 1B) is a 5'-3' exonuclease with critical roles in telomere maintenance and DNA damage response 1. The protein functions primarily in protecting telomeres from non-homologous end-joining (NHEJ)-mediated fusion by generating 3' single-stranded overhangs at leading-end telomeres through its exonuclease activity [UniProt]. DCLRE1B operates downstream of DNA-PK signaling, which phosphorylates and positions the protein at telomeric DNA ends to regulate leading-end telomere resection, analogous to DNA-PK regulation of Artemis during V(D)J recombination 1. Beyond telomere functions, DCLRE1B participates in interstrand cross-link (ICL) repair and responds to replicative DNA damage 2. Unexpectedly, DCLRE1B exhibits beta-lactamase activity, hydrolyzing penicillin G and nitrocefin but not cephalosporins or carbapenems [UniProt]. Germline DCLRE1B mutations cause dyskeratosis congenita, an autosomal recessive bone marrow failure syndrome involving telomere dysfunction 3. p53 represses DCLRE1B expression through the DREAM repressor complex, linking telomere defects to p53-mediated cell cycle control 3. In cancer contexts, DCLRE1B emerges as a prognostic biomarker with complex roles: elevated DCLRE1B correlates with poor prognosis in melanoma and pancreatic cancer, promotes tumor cell proliferation and migration, and associates with immune infiltration patterns 452. Genetic variants in DCLRE1B show protective associations against multiple cancers 6. DCLRE1B expression is regulated by METTL3-mediated m6A modification and influences immunotherapy response 2, suggesting therapeutic targeting potential.