NUDT16L1, also known as Tudor-interacting repair regulator (TIRR) or Syndesmos, functions as a key regulator of DNA double-strand break repair pathway choice through its interaction with TP53BP1 (53BP1). In the absence of DNA damage, NUDT16L1 binds to the tandem Tudor-like domain of 53BP1, masking its histone H4K20me2-binding region and preventing 53BP1 recruitment to chr16 1. Following DNA damage, ATM-induced phosphorylation of 53BP1 and RIF1 recruitment causes NUDT16L1 dissociation, allowing 53BP1 recruitment to DNA double-strand breaks and promoting non-homologous end joining repair 1. NUDT16L1 also functions as an RNA-binding protein, with high affinity for the long non-coding RNA NEAT1, particularly its short isoform NEAT1_1, which destabilizes the TIRR/53BP1 complex in a cell cycle-dependent manner 2. Additionally, NUDT16L1 regulates translation by associating with polyribosomes and controlling the expression of mRNAs involved in primary cilia biogenesis 3. Clinically, NUDT16L1 deletion enhances tumor suppressor activity and provides cancer protection, though it causes metabolic dysfunction including insulin resistance 4. The protein has been identified as a potential biomarker in osteoarthritis and shows promise as a target for enhancing genome editing efficiency 5.