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

Petro Starokadomskyy, Terry Gemelli, Jonathan J. Rios, Chao Xing, Richard C. Wang, Haiying Li, Vladislav Pokatayev, Igor Dozmorov, Shaheen Khan, Naoteru Miyata, Guadalupe Fraile, Prithvi Raj, Zhe Xu, Zigang Xu, Lin Ma, Zhimiao Lin, Huijun Wang, Yong Yang, Dan Ben-Amitai, Naama OrensteinHuda Mussaffi, Eulalia Baselga, Gianluca Tadini, Eyal Grunebaum, Adrijan Sarajlija, Konrad Krzewski, Edward K. Wakeland, Nan Yan, Maria Teresa De La Morena, Andrew R. Zinn, Ezra Burstein

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)495-504
Number of pages10
JournalNature immunology
Volume17
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Starokadomskyy, P., Gemelli, T., Rios, J. J., Xing, C., Wang, R. C., Li, H., Pokatayev, V., Dozmorov, I., Khan, S., Miyata, N., Fraile, G., Raj, P., Xu, Z., Xu, Z., Ma, L., Lin, Z., Wang, H., Yang, Y., Ben-Amitai, D., ... Burstein, E. (2016). DNA polymerase-α regulates the activation of type i interferons through cytosolic RNA:DNA synthesis. Nature immunology, 17(5), 495-504. https://doi.org/10.1038/ni.3409