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Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress
Cecilia Domínguez Conde, … , Mirjam van der Burg, Kaan Boztug
Cecilia Domínguez Conde, … , Mirjam van der Burg, Kaan Boztug
Published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4194-4206. https://doi.org/10.1172/JCI128903.
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Research Article Genetics Immunology

Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress

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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.

Authors

Cecilia Domínguez Conde, Özlem Yüce Petronczki, Safa Baris, Katharina L. Willmann, Enrico Girardi, Elisabeth Salzer, Stefan Weitzer, Rico Chandra Ardy, Ana Krolo, Hanna Ijspeert, Ayca Kiykim, Elif Karakoc-Aydiner, Elisabeth Förster-Waldl, Leo Kager, Winfried F. Pickl, Giulio Superti-Furga, Javier Martínez, Joanna I. Loizou, Ahmet Ozen, Mirjam van der Burg, Kaan Boztug

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Figure 4

Polymerase δ mutation leads to replication-related DNA lesions associated with activation of the S-phase checkpoint.

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Polymerase δ mutation leads to replication-related DNA lesions associate...
(A) Immunoblot analysis of CHK1 phosphorylation at Ser345 in HD and P1 fibroblasts upon treatment with 2 mM hydroxyurea (HU). Total CHK1 and p-CHK1 were run on 2 different gels. GAPDH was used as a sample-processing control. (B) Immunofluorescence staining of p-RPA (Ser33) and γH2AX in HD and P1 fibroblasts. Original magnification, ×40. (C) Quantification of p-RPA (Ser33) foci per nucleus. Average of p-RPA (Ser33) foci: 17.48 (HD) and 26.11 (P1). (D) Quantification of γH2AX foci per nucleus. Average of γH2AX foci: 5.61 (HD) and 17.71 (P1). Number of cells counted in C and D: 481 (HD) and 223 (P1). (E) Immunofluorescence analysis of RAD51 foci and PCNA (S-phase marker) in HD and P1 fibroblasts. Original magnification, ×40. (F) Quantification of RAD51 foci per nucleus. Number of cells counted: 415 (HD) and 273 (P1). Image analysis was performed using CellProfiler, version 2.0.

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