Phospho-DNA-PKcs (Ser2056) Recombinant Rabbit mAb (S-3813)

Phospho-DNA-PKcs (Ser2056) is a specific post-translational modification of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) at serine 2056, serving as a critical hallmark of DNA-PKcs activation and the initiation of non-homologous end joining (NHEJ) repair. This phosphorylation event is primarily driven by DNA-PKcs autophosphorylation and represents an early and rapid response to DNA double-strand breaks induced by ionizing radiation or chemotherapeutic agents. Its upstream regulatory network is intricate: NEDDylation mediated by HUWE1 is a prerequisite licensing event for efficient phosphorylation at this site, whereas BRCA1, through its BRCT domain, directly binds DNA-PKcs and blocks Ser2056 autophosphorylation specifically in S-phase cells, thereby temporospatially suppressing NHEJ and channeling repair toward homologous recombination. Functionally, this modification not only drives conformational changes that promote DNA-PKcs dissociation from broken DNA ends to facilitate repair complex disassembly but also serves, in the genetic context of XLF deficiency, as a critical safeguard for end-joining fidelity during physiological V(D)J recombination in lymphocytes. Notably, Ser2056 phosphorylation exhibits remarkable non-canonical functional diversity: during mitosis, this modification occurs independently of DNA damage and the Ku heterodimer, localizing to centrosomes and the spindle apparatus to ensure proper chromosomal segregation. In the late stages of genotoxic stress, phosphorylated DNA-PKcs (Ser2056) dissociates from break sites and relocalizes to nuclear speckles, where it colocalizes with splicing factors and directly participates in the alternative splicing of pre-mRNA—establishing a direct link between DNA damage signaling and RNA metabolism. Clinically, this phospho-form is markedly upregulated and chromatin-bound in RET proto-oncogene-driven constitutively active medullary thyroid carcinoma, directly mediating chemoresistance. Meanwhile, the novel radiosensitizer black phosphorus quantum dots physically bind DNA-PKcs and specifically inhibit Ser2056 autophosphorylation, causing persistent stalling of repair complexes at damage sites and synergizing with ionizing radiation to induce apoptosis in renal cell carcinoma models.