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

During transcription, the mRNAmay 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 dea...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-10, Vol.114 (41), p.10942-10947
Main Authors: García-Benítez, Francisco, Gaillard, Hélène, Aguilera, Andrés
Format: Article
Language:English
Subjects:
Activation-induced cytidine deaminase
Biological Sciences
Chromatin
Cytidine deaminase
Deoxyribonucleic acid
DNA
Fungi
Gating
Genes
Genomes
Genomic instability
Hybridization
Hybrids
mRNA stability
Mutants
Nuclear pores
Pores
Proteins
Ribonuclease H1
Ribonucleic acid
RNA
Saccharomyces cerevisiae
Stability
Tethering
Transcription
Transcription factors
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Summary:During transcription, the mRNAmay 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 mlp/12 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 mlp1Δ cells. The same occurred in THO-deficient hpr1Δ cells. We conclude that proximity of transcribed chromatin to the nuclear pore helps restrain pathological R loops.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1707845114