4.8 Article

DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis

Journal

NATURE
Volume 579, Issue 7798, Pages 291-+

Publisher

NATURE RESEARCH
DOI: 10.1038/s41586-020-2041-2

Keywords

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Funding

  1. Damon Runyon Cancer Research Foundation
  2. Howard Hughes Medical Institute
  3. Pew Charitable Trusts
  4. Charles H. Hood Foundation
  5. March of Dime Foundation
  6. Charles E. Reed Faculty Initiative
  7. Irwin and Helen Sizer Career Development Professorship
  8. NIH/NCI Cancer Center Support Grant [P30CA013696]
  9. [R01CA184187]
  10. [R01CA158073]
  11. [CA215067]
  12. [1F31CA183504]

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The DNA-dependent protein kinase (DNA-PK), which comprises the KU heterodimer and a catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor(1). KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. KU also binds to RNA, but the relevance of this interaction in mammals is unclear. Here we use mouse models to show that DNA-PK has an unexpected role in the biogenesis of ribosomal RNA (rRNA) and in haematopoiesis. The expression of kinase-dead DNA-PKcs abrogates cNHEJ(2). However, most mice that both expressed kinase-dead DNA-PKcs and lacked the tumour suppressor TP53 developed myeloid disease, whereas all other previously characterized mice deficient in both cNHEJ and TP53 expression succumbed to pro-B cell lymphoma(3). DNA-PK autophosphorylates DNA-PKcs, which is its best characterized substrate. Blocking the phosphorylation of DNA-PKcs at the T2609 cluster, but not the S2056 cluster, led to KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells and caused bone marrow failure in mice. KU drives the assembly of DNA-PKcs on a wide range of cellular RNAs, including the U3 small nucleolar RNA, which is essential for processing of 18S rRNA(4). U3 activates purified DNA-PK and triggers phosphorylation of DNA-PKcs at T2609. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit processome. Together our data show that DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster.

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