Ask about this productRelated genes to: POLE4 antibody
- Gene:
- POLE4 NIH gene
- Name:
- DNA polymerase epsilon 4, accessory subunit
- Previous symbol:
- -
- Synonyms:
- p12
- Chromosome:
- 2p12
- Locus Type:
- gene with protein product
- Date approved:
- 2002-07-08
- Date modifiied:
- 2016-07-11
Related products to: POLE4 antibody
Related articles to: POLE4 antibody
- The maintenance of genome stability requires efficient leading strand synthesis by DNA Polymerase Epsilon (Polε). By performing CRISPR genetic screens in cells lacking the POLE4 subunit of Polε we define a genetic map of the factors required to support Polε function in the absence of its accessory subunits. A set of genes involved in iron metabolism emerge as required to sustain Iron Sulphur Cluster (ISC)-dependent Polε activity. We then dissect a synthetic lethal interaction between POLE3-POLE4 and the CHTF18-RFC2/5 complex. By combining cell biology, structural modelling and biochemistry, we define the existence of two tiers of regulation of Polε processivity: leading strand-specific loading of PCNA by CHTF18-RFC2/5 and "gripping" of newly synthesised dsDNA by POLE3-POLE4. The combined loss of these functions is incompatible with leading strand synthesis and viability. In summary, we describe the biochemical basis of human leading strand synthesis and the consequence of its dysfunction in genome stability. - Source: PubMed
Publication date: 2025/12/04
Agnarelli AlessandroBuckley-Benbow LaurynOzgencil MeryemLad MelanieAmpah Khamal KwesiKalinka AlexBelan OndrejMaslen SarahSkehel Mark JWalter DavidDay MatthewBellelli Roberto - Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research. - Source: PubMed
Publication date: 2025/11/29
Tayani Pour FarnazSaadatpour FatemehSalari Ali - In mammalian cells, MCM2 and POLE3/4 safeguard the symmetrical segregation of parental histones to the leading and lagging strands of newly synthesized DNA. However, the identity of additional proteins involved in parental histone distribution remains elusive. We used TurboID proximity labeling to identify interaction partners of MCM2 and POLE3/4 in mouse cells. This approach provided a candidate protein library potentially involved in the MCM2 and POLE3/POLE4-mediated process of parental histone segregation. DNA polymerase δ subunit 3 (POLD3) was a protein whose intensity differed between the interactomes of wild-type MCM2 and its histone-binding mutant. We showed POLD3 bound to both MCM2 and the histone (H3-H4) tetramers. Moreover, MCM2's histone binding affected interactions between POLD3 and histone H3. More importantly, POLD3 was required for the symmetrical transfer of parental histones H3-H4 to the leading and lagging strands of newly synthesized DNA in mouse cells. In short, our findings establish that POLD3 forms a protein complex with MCM2 and histone (H3-H4) tetramers, functioning as a novel histone chaperone to regulate parental histone segregation in mammalian cells. - Source: PubMed
Publication date: 2025/11/27
Sun YapingLiang XiaoyanLiu FangZhao WenjuanZhou JiaqiLi YueYao YuanZhang ZiweiLi GangChan KuimingZhang DaoqinWang ZhiquanGao YuanYu ChuanheWu YuchunKang XingQiu LingyuLi NanGan Haiyun - Radiation-induced skin injury (RSI) is characterized by persistent mitochondrial dysfunction and compromised DNA repair mechanisms, posing significant challenges for clinical management. To address this, we engineered mitochondria-enriched nanovesicles (NVs) derived from human umbilical cord mesenchymal stem cells (hUMSCs), designed to deliver bioactive mitochondrial components to irradiated skin tissues. Using established in vitro and in vivo models of X-ray-induced RSI, we demonstrated efficient NV internalization into epidermal and dermal cells, leading to restoration of mitochondrial ultrastructure and metabolic function, attenuation of reactive oxygen species (ROS), and facilitation of DNA damage repair. Data-independent acquisition (DIA) proteomic profiling further indicated that NVs significantly upregulated key DNA repair proteins (including POLD3, POLE4, RFC1, and ERCC6), which were downregulated after irradiation, and activated the PINK1-Parkin mitophagy pathway. Additionally, NVs restored mitochondrial dynamics by suppressing DRP1-mediated fission and enhancing MFN1/2-dependent fusion, collectively promoting cellular homeostasis. These findings support the development of a cell-free, mitochondria-based nanotherapeutic strategy that concurrently targets DNA repair and mitochondrial quality control, presenting a scalable and promising treatment for RSI and potentially other radiation-induced disorders. - Source: PubMed
Publication date: 2025/10/08
Zhu MengruXia JunhaoLiu JiaZou WeiGuan XinWang LizhiWang YichenWang BingWang FengyaZhang QingwenHe KemanLiu LukuanLiu Jing - Despite WWOX's established role as a tumor suppressor, conclusive evidence linking germline WWOX loss-of-function variants to oncogenesis remains scarce. Two germline homozygous WWOX missense variants (p.P252A and p.P282A) are identified in a patient with histological mixed-type thyroid cancer. In vitro and in vivo functional assays demonstrate that both WWOX and WWOX mutants exhibit complete loss of tumor-suppressive activity, failing to inhibit tumor cell growth and invasion. The WWOX mutant undergo accelerated degradation via HSC70 chaperone-mediated autophagy in the lysosome. Furthermore, both P252A and P282A variants impair the WWOX protein's critical role in DNA damage repair. A nucleotide excision repair-related protein, POLE4, is identified to interact with WWOX, but not with the WWOX mutant. Finally, low WWOX expression is found to be associated with epithelial-mesenchymal transition and aggressive phenotype in thyroid cancer. These findings provide the first genetic and functional evidence that germline WWOX loss-of-function variants drive cancer pathogenesis by perturbing multiple tumor-suppressive mechanisms. - Source: PubMed
Publication date: 2025/10/22
Zhang XiaopengQi JianWang JialiangWang ZhipengWang YongguangHu ZongtaoXu AoHong BoWang Hongzhi