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Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10942-10947. doi: 10.1073/pnas.1707845114. Epub 2017 Sep 25.

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

Author information

1
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Universidad de Sevilla, 41092 Seville, Spain.
2
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Universidad de Sevilla, 41092 Seville, Spain gaillard@us.es aguilo@us.es.

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.

KEYWORDS:

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

PMID:
28973905
PMCID:
PMC5642707
DOI:
10.1073/pnas.1707845114
[Indexed for MEDLINE]
Free PMC Article

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