SHLD3 is a core subunit of the shieldin complex, which protects DNA double-strand breaks (DSBs) to promote non-homologous end joining (NHEJ) repair 1. As a component of the four-subunit shieldin complex (REV7, SHLD1, SHLD2, and SHLD3), SHLD3 functions downstream of 53BP1 and RIF1 during G1 and S phase to suppress DNA end resection and inhibit homologous recombination 1. SHLD3 recruits REV7 through specific structural interactions involving its REV7-binding domain, with both the N-terminal loop and C-terminal α-helix essential for high-affinity binding 2. The shieldin complex localizes to DSB sites in a 53BP1-dependent manner, where SHLD2's OB-fold domains bind single-stranded DNA to physically shield broken DNA ends from nucleolytic degradation 1. SHLD3 also mediates conformational heterodimerization of REV7, creating a closed/open REV7 dimer critical for complex assembly and NHEJ efficiency 3. The shieldin complex regulates immunoglobulin class-switch recombination and promotes PARP inhibitor sensitivity in BRCA1-deficient cells by preventing excessive resection 1. TRIP13 AAA+ ATPase can disassemble shieldin through ATP-dependent remodeling of the SHLD3-REV7 interface, providing a mechanism for dynamic control of DNA repair pathway choice 4. Dysregulation of SHLD3 function is associated with PARP inhibitor resistance in homologous recombination-deficient tumors.