The NF90/NF45 complex participates in DNA break repair via nonhomologous end joining

Raghavendra A. Shamanna, Mainul Hoque, Anita Lewis-Antes, Edouard I. Azzam, David Lagunoff, Tsafi Pe'ery, Michael B. Mathews

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Nuclear factor 90 (NF90), an RNA-binding protein implicated in the regulation of gene expression, exists as a heterodimeric complex with NF45. We previously reported that depletion of the NF90/NF45 complex results in a multinucleated phenotype. Time-lapse microscopy revealed that binucleated cells arise by incomplete abscission of progeny cells followed by fusion. Multinucleate cells arose through aberrant division of binucleated cells and displayed abnormal metaphase plates and anaphase chromatin bridges suggestive of DNA repair defects. NF90 and NF45 are known to interact with the DNA-dependent protein kinase (DNA-PK), which is involved in telomere maintenance and DNA repair by nonhomologous end joining (NHEJ). We hypothesized that NF90 modulates the activity of DNA-PK. In an in vitro NHEJ assay system, DNA end joining was reduced by NF90/NF45 immunodepletion or by RNA digestion to an extent similar to that for catalytic subunit DNA-PKcs immunodepletion. In vivo, NF90/NF45-depleted cells displayed increased γ-histone 2A.X foci, indicative of an accumulation of double-strand DNA breaks (DSBs), and increased sensitivity to ionizing radiation consistent with decreased DSB repair. Further, NF90/NF45 knockdown reduced end-joining activity in vivo. These results identify the NF90/NF45 complex as a regulator of DNA damage repair mediated by DNA-PK and suggest that structured RNA may modulate this process.

Original languageEnglish (US)
Pages (from-to)4832-4843
Number of pages12
JournalMolecular and cellular biology
Volume31
Issue number23
DOIs
StatePublished - Dec 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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