DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis PMID: 27019227

ADC Targets in Oncology

2026-04-10

DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis

Nat Immunol. 2016 May;17(5):495-504. doi: 10.1038/ni.3409.

Petro Starokadomskyy ¹ , Terry Gemelli ² , Jonathan J Rios ² ³ ⁴ , Chao Xing ² ⁵ , Richard C Wang ⁶ , Haiying Li ¹ , Vladislav Pokatayev ¹ , Igor Dozmorov ⁷ , Shaheen Khan ⁷ , Naoteru Miyata ¹ , Guadalupe Fraile ⁸ , Prithvi Raj ⁷ , Zhe Xu ⁹ , Zigang Xu ⁹ , Lin Ma ⁹ , Zhimiao Lin ¹⁰ , Huijun Wang ¹⁰ ¹¹ ¹² , Yong Yang ¹⁰ ¹¹ , Dan Ben-Amitai ¹³ ¹⁴ , Naama Orenstein ¹⁵ , Huda Mussaffi ¹⁴ ¹⁶ , Eulalia Baselga ¹⁷ , Gianluca Tadini ¹⁸ ¹⁹ , Eyal Grunebaum ²⁰ ²¹ , Adrijan Sarajlija ²² ²³ , Konrad Krzewski ²⁴ , Edward K Wakeland ⁷ , Nan Yan ¹ ²⁵ , Maria Teresa de la Morena ¹ ⁴ ²⁶ , Andrew R Zinn ¹ ² , Ezra Burstein ¹ ²⁷

Affiliations

1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2. Eugene McDermott Center for Human Growth &Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3. Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
4. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
6. Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
8. Department of Internal Medicine, Ramón y Cajal University Hospital, Madrid, Spain.
9. Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
10. Department of Dermatology, Peking University First Hospital, Beijing, China.
11. Peking-Tsinghua Center for Life Sciences, Beijing, China.
12. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
13. Unit of Pediatric Dermatology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
14. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
15. Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
16. Pulmonology Institute, Schneider Children's Medical Center, Petach Tikva, Israel.
17. Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
18. Pediatric Dermatology Unit and Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
19. IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
20. Developmental &Stem Cell Biology Program, Hospital for Sick Children, Toronto, Canada.
21. Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Canada.
22. Mother and Child Health Care Institute of Serbia, Belgrade, Serbia.
23. School of Medicine, University of Belgrade, Belgrade, Serbia.
24. Laboratory of Immunogenetics, Receptor Cell Biology Section, NIAID, NIH, Rockville, Maryland, USA.
25. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
26. Children's Health, Dallas, Texas, USA.
27. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Abstract

Aberrant nucleic acids generated during viral replication are the main trigger for Antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.