title: DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Petro
authors.initials: P
authors.lastname: Starokadomskyy
authors.affiliation: Eugene McDermott Center for Human Growth &Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Gemelli
authors.affiliation: Eugene McDermott Center for Human Growth &Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Rios
authors.affiliation: Eugene McDermott Center for Human Growth &Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Pokatayev
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Naoteru
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Department of Internal Medicine, Ramón y Cajal University Hospital, Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Fraile
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Raj
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.
authors.forename: Zhimiao
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.|Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Unit of Pediatric Dermatology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Ben-Amitai
authors.affiliation: Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Orenstein
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Pulmonology Institute, Schneider Children's Medical Center, Petach Tikva, Israel.
authors.forename: Huda
authors.initials: H
authors.lastname: Mussaffi
authors.affiliation: Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Eulalia
authors.initials: E
authors.lastname: Baselga
authors.affiliation: Pediatric Dermatology Unit and Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tadini
authors.affiliation: Developmental &Stem Cell Biology Program, Hospital for Sick Children, Toronto, Canada.|Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Eyal
authors.initials: E
authors.lastname: Grunebaum
authors.affiliation: Mother and Child Health Care Institute of Serbia, Belgrade, Serbia.|School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Adrijan
authors.initials: A
authors.lastname: Sarajlija
authors.affiliation: Laboratory of Immunogenetics, Receptor Cell Biology Section, NIAID, NIH, Rockville, Maryland, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Krzewski
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Children's Health, Dallas, Texas, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: de la Morena
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Eugene McDermott Center for Human Growth &Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Andrew R
authors.identifier: http://orcid.org/0000-0002-4935-3291
authors.initials: AR
authors.lastname: Zinn
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis* / Q000235:genetics; D004256:DNA Polymerase I / Q000235:genetics / Q000378:metabolism*; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010859:Pigmentation Disorders / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007370:Interferon Type I; D012313:RNA; D004247:DNA; D004256:DNA Polymerase I