Ask about this productRelated genes to: XRCC4 antibody
- Gene:
- XRCC4 NIH gene
- Name:
- X-ray repair cross complementing 4
- Previous symbol:
- -
- Synonyms:
- -
- Chromosome:
- 5q14.2
- Locus Type:
- gene with protein product
- Date approved:
- 1990-10-16
- Date modifiied:
- 2016-06-02
Related products to: XRCC4 antibody
Related articles to: XRCC4 antibody
- Mislocalization and aggregation of the DNA/RNA binding protein, TDP-43, is seen in most cases of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Accumulating DNA damage in neurons is also a common feature of ALS-FTD. TDP-43 has several characterized roles in the regulation of the DNA damage response (DDR). This review systematically explored the relationship between TDP-43, DNA damage and the DNA damage response in various models of ALS-FTD, facilitating comparison of findings between studies using similar models. Twelve peer-reviewed papers, covering eight TDP-43 mutations out of nearly 40, were reviewed and five experimental models included: cell lines, patient-derived iPS cells, organoids, and rodent models, plus post-mortem cortex and spinal cord tissue from ALS-FTD patients. Across the studies and models, depletion of TDP-43 or ALS-linked mutations consistently increased genomic instability. Q331K-expressing cells showed a 2-3-fold reduction in DNA repair activity and a 4-6-fold increase in DDR activation, while -depleted cells showed a 20-fold rise in double strand breaks. TDP-43 normally binds to damaged chromatin, participates in early DDR signaling and scaffolds core DNA damage repair factors, including Ku70, XRCC4 and DNA ligase 4. This systematic review and narrative synthesis sheds light on mechanisms that explain how TDP-43 dysfunction impairs genome maintenance. When TDP-43 is mislocalized, mutated or aggregated, these interactions are disrupted, resulting in impaired DNA repair. DNA damage is also caused by increasing R-loops, dysregulation of mismatch repair gene transcription, and sequestering of repair proteins into cytoplasmic inclusions. Upstream DNA damage can further drive TDP-43 mislocalisation, creating a feed-forward loop. Given the ubiquity of TDP-43 pathology across neurodegenerative diseases, targeting the DDR mechanisms affected by TDP-43 may offer new therapeutic opportunities. - Source: PubMed
Publication date: 2026/03/17
Almalki SehamSalama MohamedTaylor Matthew JAhmed ZubairTuxworth Richard I - 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 - Ataxia Telangiectasia Mutated (ATM) kinase deficiency results in cancer susceptibility and drug sensitivity. Deficiency in either the BRCA1 interacting A complex or XRCC4/Ligase 4 confers resistance to Topoisomerase I or PARP1 inhibitors in ATM-deficient cells. This suggests that BRCA1-A directs toxicity to fork-damaging agents in ATM mutated cells vis-à-vis illegitimate end-joining. Here, we show that ATM inhibition triggers combined SUMO and ubiquitin mediated BRCA1-A damaged fork recognition to restrict end-resection and cause Topoisomerase I inhibitor hypersensitivity. BRCA1-A deficient cells display elevated chromatin accessibility and nuclease activity at damaged forks, coupled with restored resection and drug resistance. Electron microscopy evidence demonstrates that ATM inhibition prevents replication fork reversal, which is restored by BRCA1-A loss to generate substrates for end resection. These findings reveal that BRCA1-A enforces a restrictive chromatin state to suppress the genesis of resection substrates, implicating fork reversal as a key determinant of chemotherapy response in ATM deficient cells. - Source: PubMed
Publication date: 2026/03/22
Datta ArindamJackson JessicaMorozov Yaroslav IQiu JinghanVindigni AlessandroGreenberg Roger A - DNA double-strand breaks (DSBs) are among the most severe forms of DNA damage, and their cellular consequences depend on the efficiency of DNA repair pathways. Non-homologous end joining (NHEJ) provides a rapid mechanism to reconnect broken DNA strands and is a major pathway for maintaining genomic stability. FBXW7α is the substrate-selective unit within the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, imparting specificity by recruiting proteins destined for ubiquitin-mediated turnover. It has recently been reported to mediate XRCC4 ubiquitylation during DNA damage, and is a recognized tumor suppressor, thereby promoting NHEJ. A circular RNA derived from FBXW7 gene exons 3 and 4 (circ-FBXW7) has been identified. This circRNA encodes a 185-amino acid protein, named FBXW7-185aa, which contains a spanning-junction open reading frame (ORF). We found that compared with FBXW7α, FBXW7-185aa was recruited more slowly to DNA damage sites in glioblastoma (GBM) cells. Functionally, FBXW7-185aa may enhance NHEJ repair by facilitating the removal of FBXW7α from DNA damage lesions, thereby promoting the subsequent steps of DNA repair. Efficient DNA repair can enable tumor cells to survive genotoxic stressors like radiotherapy. Radiotherapy is also known to modulate the tumor immune microenvironment. Therefore, our findings suggest that FBXW7-185aa may represent a potential molecular nexus between DNA damage response and tumor-immune interactions. Moreover, depletion of FBXW7-185aa was associated with increased sensitivity of GBM cells to pevonedistat, a drug that inhibits the ubiquitin-like modification of the protein NEDD8, when combined with radiation. Together, our results indicate that FBXW7-185aa acts as a fine-tuning regulator of NHEJ through its interaction with FBXW7α, adding a new layer to the complexity of FBXW7 gene-derived proteins in DNA repair. These findings provide a mechanistic basis for exploring how fine-tuned DNA repair dynamics may influence GBM radiosensitivity and potentially impact tumor immunogenicity, although direct immunological effects remain to be determined. - Source: PubMed
Publication date: 2026/03/19
Li ZianHu NanZhou ShaolongGuo XuyangYang ZhuoJing ZhouLi HaoTao YiranHu WeihuaLiang WulongLi JunqiLyu YuanFu XudongWang Xinjun - For decades, there has been a strong epidemiological association between solar ultraviolet (UV) radiation and skin cancer. UVB and UVA are the major UV bands that can penetrate the atmosphere, playing vital roles in skin carcinogenesis. Our research group previously discovered that a specific dose of UVA can inhibit the increase of activator protein 1 (AP-1) activity caused by UVB. It is unclear whether UVA plays a particular role in UVB-induced skin cancer. Here, we report that UVA was protective in UVB-induced cutaneous squamous cell carcinoma (cSCC) by attenuating UVB-induced DNA damage. DNA repair chip array results showed that the mRNA level of X-ray cross-complementing protein 4 (XRCC4) significantly increased in the UVA/B group compared with the UVB group, and knockdown of XRCC4 partly blocked the protective effect of UVA in UVB-induced DNA damage. AP-1, the predicted transcriptional regulatory factor of XRCC4, exhibited no sensitivity to UVB radiation upon pretreatment with UVA. More importantly, the luciferase reporter assay showed that c-Fos, which is the critical component of AP-1, inhibited the transcription of XRCC4, and mutation of c-Fos (cys154 > serine) partly enhanced this effect and promoted keratinocyte transformation. UVA was protective in UVB-induced cSCC by interacting with the c-Fos/XRCC4 axis. - Source: PubMed
Xie YifeiYao KeWu YongfengDing CaoyuanDickinson Sally ELi JianJiang YananZhao SiminRoh EunmiriLiu KangdongDong Zigang