Terminal Deoxynucleotidyl Transferase (TdT): Properties and Functions

Terminal deoxynucleotidyl transferase (TdT) is a highly specialized DNA polymerase critical for adaptive immunity. Its primary role involves generating antigen receptor diversity through V(D)J recombination, a cornerstone of immune system functionality. This review provides an in-depth exploration of TdT's structural and functional characteristics, the distinctions between its isoforms, its catalytic mechanisms, substrate specificities, and its wide-ranging applications in biotechnology. TdT exhibits a unique ability to incorporate nucleotides at the ۳' terminus of single-stranded DNA in a template-independent manner. As a member of the Pol X family, it is characterized by a distinctive loop structure that ensures specificity for single-stranded DNA. Two isoforms of TdT, TdTL and TdTS, arise via alternative splicing, each playing distinct roles: TdTL primarily enhances junctional diversity, while TdTS appears to modulate recombination fidelity. By randomly adding nucleotides at V(D)J recombination junctions, TdT exponentially amplifies antigen receptor diversity, thereby enabling the immune system to recognize an extensive array of pathogens. Its activity is tightly regulated at both transcriptional and post-translational levels, ensuring its function aligns precisely with the developmental stages of lymphocytes. Catalysis relies on divalent metal ions, underscoring the enzyme's flexibility and compatibility with various nucleotide analogs. Beyond its physiological significance, TdT is pivotal in molecular biology and biotechnology. It underpins DNA-labeling techniques such as TUNEL and plays a critical role in synthetic biology by enabling the generation of novel DNA sequences. Aberrations in TdT expression or function can severely compromise immune diversity, leading to immunodeficiencies or hematological malignancies. A deeper understanding of its molecular mechanisms offers promising therapeutic avenues for managing immunodeficiencies, leukemia, and advancements in DNA engineering. TdT is integral to the adaptability of the immune system, seamlessly linking structural specificity to functional versatility. Continued research into its isoforms, regulation, and catalytic mechanisms highlights its profound impact on biomedicine and biotechnology. Exploring TdT's multifaceted roles further will elucidate its contributions to immune diversity, facilitate the development of innovative diagnostics, and inspire therapeutic innovations.

کلیدواژه ها:

terminal deoxynucleotidyl transferase ، V(D)J recombination ، antigen receptor diversity ، DNA polymerase ، immune system