ArticleThe Journal of clinical investigation2019
Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Pooled it
- Neurological Complications in Inborn Errors of Immunity: A Scoping Review of Clinical Spectrum, Pathophysiological Mechanisms, and Therapeutic Strategies.Clinical reviews in allergy & immunology · 2025Article
- DNA Polymerase Delta 2 Activates Cell Cycle in Lung Adenocarcinoma, Leading to High Malignancy and Poor Prognosis.Annals of surgical oncology · 2025Article
- Identification of nonsense variants in the ATM gene mimicking SCID phenotype: a brief report.Immunologic research · 2025Article
- Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients.The Journal of experimental medicine · 2025Article
- POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments.European journal of human genetics : EJHG · 2025Article
- Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations.Journal of clinical immunology · 2024Article
- Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.Journal of clinical immunology · 2023Article
- Association of Mutations in Replicative DNA Polymerase Genes with Human Disease: Possible Application ofInternational journal of molecular sciences · 2023Review
- Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Prospects of POLD1 in Human Cancers: A Review.Cancers · 2023Review
- An arrayed CRISPR screen of primary B cells reveals the essential elements of the antibody secretion pathway.Frontiers in immunology · 2023Article
- Non-canonical binding of the Chaetomium thermophilum PolD4 N-terminal PIP motif to PCNA involves Q-pocket and compact 2-fork plug interactions but no 3The FEBS journal · 2023Article
- Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia.JCI insight · 2022Article
- NovelJournal of medical genetics · 2022Article
- POLD2 is activated by E2F1 to promote triple-negative breast cancer proliferation.Frontiers in oncology · 2022Article
- An integrative analysis revealing POLD2 as a tumor suppressive immune protein and prognostic biomarker in pan-cancer.Frontiers in genetics · 2022Article
- The Mechanism and Prognostic Value of DNA Polymerase δ Subunits in Hepatocellular Carcinoma: Implications for Precision Therapy.International journal of general medicine · 2022Article
- Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair.International journal of molecular sciences · 2021Review
- The stabilized Pol31-Pol3 interface counteracts Pol32 ablation with differential effects on repair.Life science alliance · 2021Article
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 6 countries.
Funding
Abstract
Polymerase δ is essential for eukaryotic genome duplication and synthesizes DNA at both the leading and lagging strands. The polymerase δ complex is a heterotetramer comprising the catalytic subunit POLD1 and the accessory subunits POLD2, POLD3, and POLD4. Beyond DNA replication, the polymerase δ complex has emerged as a central element in genome maintenance. The essentiality of polymerase δ has constrained the generation of polymerase δ-knockout cell lines or model organisms and, therefore, the understanding of the complexity of its activity and the function of its accessory subunits. To our knowledge, no germline biallelic mutations affecting this complex have been reported in humans. In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase δ complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. Patients' cells showed impaired cell-cycle progression and replication-associated DNA lesions that were reversible upon overexpression of polymerase δ. The mutations affected the stability and interactions within the polymerase δ complex or its intrinsic polymerase activity. We believe our discovery of human polymerase δ deficiency identifies the central role of this complex in the prevention of replication-related DNA lesions, with particular relevance to adaptive immunity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.