FANCD2 protects genome stability by recruiting RNA processing enzymes to resolve R-loops during mild replication stress

FEBS J. 2019 Jan;286(1):139-150. doi: 10.1111/febs.14700. Epub 2018 Nov 27.

Abstract

R-loops, which consist of DNA : RNA hybrids and displaced single-strand DNA, are a major threat to genome stability. We have previously reported that a key Fanconi anemia protein, FANCD2, accumulates on large fragile genes during mild replication stress in a manner depending on R-loops. In this study, we found that FANCD2 suppresses R-loop levels. Furthermore, we identified FANCD2 interactions with RNA processing factors, including hnRNP U and DDX47. Our data suggest that FANCD2, which accumulates with R-loops in chromatin, recruits these factors and thereby promotes efficient processing of long RNA transcripts. This may lead to a reduction in transcription-replication collisions, as detected by PLA between PCNA and RNA Polymerase II, and hence, lowered R-loop levels. We propose that this mechanism might contribute to maintenance of genome stability during mild replication stress.

Keywords: DDX47; FANCD2; R-loops; hnRNP U; replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • DNA Repair
  • DNA Replication*
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Genomic Instability*
  • Heterogeneous-Nuclear Ribonucleoprotein U / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein U / metabolism*
  • Humans
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA, Neoplasm / chemistry
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Tumor Cells, Cultured

Substances

  • Chromatin
  • DNA, Neoplasm
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Heterogeneous-Nuclear Ribonucleoprotein U
  • RNA, Neoplasm
  • RNA Polymerase II
  • DDX47 protein, human
  • DEAD-box RNA Helicases