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Research Article

Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability

Francisco García-Benítez, Hélène Gaillard, and View ORCID ProfileAndrés Aguilera
  1. aCentro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas–Universidad Pablo de Olavide–Universidad de Sevilla, 41092 Seville, Spain

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PNAS October 10, 2017 114 (41) 10942-10947; first published September 25, 2017; https://doi.org/10.1073/pnas.1707845114
Francisco García-Benítez
aCentro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas–Universidad Pablo de Olavide–Universidad de Sevilla, 41092 Seville, Spain
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Hélène Gaillard
aCentro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas–Universidad Pablo de Olavide–Universidad de Sevilla, 41092 Seville, Spain
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  • For correspondence: gaillard@us.es aguilo@us.es
Andrés Aguilera
aCentro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas–Universidad Pablo de Olavide–Universidad de Sevilla, 41092 Seville, Spain
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  • ORCID record for Andrés Aguilera
  • For correspondence: gaillard@us.es aguilo@us.es
  1. Edited by Kevin Struhl, Harvard Medical School, Boston, MA, and approved August 29, 2017 (received for review May 11, 2017)

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Significance

During transcription, the mRNA may hybridize back with its template DNA, forming a structure called R loop. These structures have been associated with genome instability and human disease. Using budding yeast as a model organism to screen for new genes preventing R loops, we identified MLP1 and subsequently showed that the nuclear basket protein Mlp1/2 has a role in preventing R loop formation and genome instability in yeast. Our work indicates that R loops are formed in the nucleoplasm and that proximity of transcribed chromatin to the nuclear pore constrains R loop formation. Our study opens additional perspectives to understand the role of RNA in the control of genome integrity as a function of nuclear location.

Abstract

During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the mechanism by which eukaryotic cells prevent harmful R loops, we used human activation-induced cytidine deaminase (AID) to identify genes preventing R loops. A screening of 400 Saccharomyces cerevisiae selected strains deleted in nuclear genes revealed that cells lacking the Mlp1/2 nuclear basket proteins show AID-dependent genomic instability and replication defects that were suppressed by RNase H1 overexpression. Importantly, DNA–RNA hybrids accumulated at transcribed genes in mlp1/2 mutants, indicating that Mlp1/2 prevents R loops. Consistent with the Mlp1/2 role in gene gating to nuclear pores, artificial tethering to the nuclear periphery of a transcribed locus suppressed R loops in mlp1∆ cells. The same occurred in THO-deficient hpr1∆ cells. We conclude that proximity of transcribed chromatin to the nuclear pore helps restrain pathological R loops.

  • nuclear pores
  • transcription
  • R loop
  • genome instability
  • Mpl1/2

Footnotes

  • ↵1To whom correspondence may be addressed. Email: gaillard{at}us.es or aguilo{at}us.es.
  • Author contributions: F.G.-B., H.G., and A.A. designed research; F.G.-B. and H.G. performed research; F.G.-B., H.G., and A.A. analyzed data; and H.G. and A.A. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1707845114/-/DCSupplemental.

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Nuclear pore proximity prevents R loop formation
Francisco García-Benítez, Hélène Gaillard, Andrés Aguilera
Proceedings of the National Academy of Sciences Oct 2017, 114 (41) 10942-10947; DOI: 10.1073/pnas.1707845114

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Nuclear pore proximity prevents R loop formation
Francisco García-Benítez, Hélène Gaillard, Andrés Aguilera
Proceedings of the National Academy of Sciences Oct 2017, 114 (41) 10942-10947; DOI: 10.1073/pnas.1707845114
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Proceedings of the National Academy of Sciences: 114 (41)
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