N4BP2 (NEDD4 binding protein 2) is a cytoplasmic endonuclease with 5'-polynucleotide kinase and nicking endonuclease activity. It participates in DNA repair or recombination and plays a role in non-stop mRNA decay, which targets mRNAs lacking proper stop codons. Recently, N4BP2 was identified as a key nuclease that enters ruptured micronuclei in cancer cells, initiating DNA damage and chromosome 4 that drives genome instability including chr4 and extrachromosomal DNA formation 1. Elevated N4BP2 expression predicts chr4 and copy number amplifications across human cancer genomes 1. In nasopharyngeal carcinoma, specific N4BP2 haplotype blocks (ATTA and GTTG) are associated with increased disease risk in Southern Chinese populations, and N4BP2 expression is elevated in tumor tissues 2. A transcriptome-wide association study identified N4BP2 among novel blood-based candidate susceptibility genes for prostate cancer risk 3. In pediatric adrenocortical tumors, N4BP2 overexpression is associated with poorer five-year event-free survival 4. N4BP2 has also been identified as a potential partner gene in recurrent 9p24.1 translocations in lymphoid malignancies 5. Low-frequency coding variants in N4BP2 increase risk for nonsyndromic cleft lip with or without cleft palate 6.