Immunological and genetic characterization of paediatric patients with immune deficiency syndromes Araştırıcılar Kaan Boztug Işıl Barlan Safa Barış Ahmet Özen Elif Karakoç Aydiner

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Özen A. O. , Barış S. , Aydıner E. , Boztug K.(Executive)

Other Supported Projects, 2013 - 2023

  • Project Type: Other Supported Projects
  • Begin Date: January 2013
  • End Date: January 2023

Project 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.