Ask about this productRelated genes to: LIG4 antibody
- Gene:
- LIG4 NIH gene
- Name:
- DNA ligase 4
- Previous symbol:
- -
- Synonyms:
- -
- Chromosome:
- 13q33.3
- Locus Type:
- gene with protein product
- Date approved:
- 1995-08-10
- Date modifiied:
- 2019-04-23
Related products to: LIG4 antibody
Related articles to: LIG4 antibody
- V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical non-homologous end-joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEI), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase (RAG1, RAG2, and the recently identified RAG co-chaperone NudC domain-containing 3, NUDCD3), end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development. - Source: PubMed
Publication date: 2026/03/28
Schim van der Loeff InaAhuja ManishaChen RuiPatane EleonoraHambleton Sophie - The stem cell factor SOX2 can reprogram resident glial cells into neurons in the adult mammalian central nervous system, but the molecular mechanisms underlying this process remain poorly understood. Here, we show that both SOX2 phosphorylation and the PRKDC-dependent nonhomologous end joining (NHEJ) pathway are essential for SOX2-mediated in vivo glia-to-neuron reprogramming. A phospho-mimetic SOX2 mutant significantly enhances reprogramming output without altering neuronal fate. Conversely, loss of PRKDC or knockdown of core NHEJ components KU80 and LIG4 abolishes reprogramming. Notably, p53 knockdown restores reprogramming in PRKDC-deficient mice, likely by overcoming DNA damage-induced cell-cycle arrest. These findings demonstrate that SOX2-driven glial reprogramming requires both precise posttranslational regulation and effective DNA damage repair and suggest that targeting these pathways could enhance regenerative strategies in the CNS. - Source: PubMed
Publication date: 2026/03/17
Zhong XiaolingZou YuhuaZhang Chun-Li - Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and α-synuclein aggregation, with evidence implicating impaired DNA double-strand break (DSB) repair in disease pathogenesis. This study aimed to systematically evaluate the association between genetic polymorphisms in DSB repair pathway genes, including , , , , , , , and , and PD risk, along with corresponding mRNA expression and DNA repair capacity. A total of 123 clinically diagnosed PD patients and 492 age- and sex-matched healthy controls of Taiwanese ancestry were genotyped, and transcriptional and functional assays were performed in 52 healthy controls. Nominally significant associations with PD risk were identified for four SNPs: rs5751129 ( = 3.55 × 10⁻⁵), rs28360071 ( = 0.0181), rs2735383 ( = 0.0213) and rs17772583 ( = 0.0411). Among these, rs5751129 remained statistically significant after correction for multiple comparisons. Compared to individuals with the wild-type TT genotype, carriers of the heterozygous variant (TC) and homozygous variant (CC) genotypes exhibited increased PD risks, with odds ratios of 1.86 (95% CI, 1.09–3.17) and 13.82 (95% CI, 2.74–69.54), respectively. Cumulative analysis revealed a dose-dependent increase in PD risk with multiple high-risk genotypes ( for trend = 0.0025). Functionally, the rs5751129 CC variant was associated with reduced mRNA expression ( = 0.0001) and impaired NHEJ and DSB repair capacity ( = 0.0183). These findings suggest that genetic variants in DSB genes , , and are associated with PD susceptibility in a Taiwanese population and provide preliminary functional evidence that variants contribute to compromised DNA repair. Together, the results highlight a critical role of inherited DSB repair deficiencies in PD etiology and suggest potential avenues for personalized risk prediction and prevention. - Source: PubMed
Publication date: 2026/03/11
Chen Chao-HsuanTsai Chia-WenChang Wen-ShinLu Ming-KueiCho Der-YangBau Da-Tian - Extrachromosomal circular DNA (ecDNA) is frequently generated within the nucleus, contributing to genome dynamics and heterogeneity, thereby promoting cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here, using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes as key drivers of ecDNA production. Following DNA segmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively mediates ecDNA production by joining the free ends of the DNA fragments. Furthermore, ecDNA from patient tumors harbors junction sites with a LIG4 signature. Notably, disruption of either LIG4 or the BRCA1-A complex in cancer cells impairs ecDNA-mediated adaptation, hindering the development of resistance to both chemotherapy and targeted therapies. Together, our study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers therapeutic targets to block ecDNA-mediated adaptation for cancer treatment. - Source: PubMed
Publication date: 2026/03/11
Chung Oliver WYao ShunWang LingYang FuSchier LaurenAldana MelissaCerda-Smith ChristianHutchinson Haley MWood Kris CSu WeijiaKhasraw MustafaZou LeeRamsden Dale AZhang Zz Zhao - DNA double-strand breaks (DSBs), the most lethal DNA lesions, are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ). Caffeine is known to inhibit HR by displacing Rad51 from single-stranded DNA, but its impact on NHEJ was unclear. Here, we show that caffeine inhibits NHEJ in a concentration-dependent manner using biochemical and cellular assays. Increased 53BP1 and γ-H2AX foci upon caffeine exposure indicate inhibition of chromosomal NHEJ, leading to accumulation of DSBs. γ-H2AX immunofluorescence, neutral comet, and TUNEL assays revealed persistent DNA breaks and reduced repair. Mechanistically, in silico, biophysical, and biochemical analyses demonstrate that caffeine directly binds to XRCC4, disrupting its interaction with DNA ligase IV and thereby inhibiting repair. Biolayer interferometry confirmed caffeine-XRCC4 binding, with mutation of Thr133 reducing caffeine affinity and impairing XRCC4 recruitment to γ-H2AX-marked DSBs. Disruption of the predicted caffeine interaction site in XRCC4 (T133A) partially restored end joining in the presence of caffeine. Clonogenic survival assays showed decreased survival after caffeine treatment, more prominently in wild-type than in ligase IV-deficient cells. Immunodepletion and reconstitution experiments confirmed that caffeine specifically targets the ligase IV/XRCC4 complex. Thus, caffeine suppresses NHEJ by directly inhibiting ligase IV/XRCC4-mediated DNA end joining. - Source: PubMed
Kumari SusmitaSathees DivyaRai Prashant KumarSahu Lipsa RaniRaghavan Sathees C