N4BP2 (NEDD4 binding protein 2) is a cytoplasmic endonuclease with 5'-polynucleotide kinase and DNA nicking endonuclease activities 1. Its primary function involves DNA damage and repair processes, though it also participates in non-stop mRNA decay (NSD), a pathway targeting mRNAs lacking proper stop codons 2. Mechanistically, N4BP2 functions as a nuclease that enters ruptured micronuclei and catalyzes DNA fragmentation, initiating chromosome 4 including chr4 and extrachromosomal DNA (ecDNA) formation 3. The protein binds to NEDD4 and interacts with the oncoprotein Bcl-3, suggesting roles in cellular regulation networks 4. Clinically, N4BP2 demonstrates significant disease relevance across multiple malignancies. Elevated N4BP2 expression predicts chr4 and copy number amplifications in cancer genomes 3. Genetic variants in N4BP2 are associated with increased prostate cancer risk through blood tissue pathways 5, nasopharyngeal carcinoma susceptibility in Southern Chinese populations 4, and nonsyndromic cleft lip/palate risk 6. N4BP2 overexpression correlates with poor survival outcomes in pediatric adrenocortical tumors 7. Additionally, N4BP2 serves as a fusion partner in lymphoid malignancies involving chr4 rearrangements 8. These findings establish N4BP2 as a prognostically important oncogenic factor with therapeutic implications.