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Genes Dev. 2013 Nov 15;27(22):2445-58. doi: 10.1101/gad.229880.113.

The Npl3 hnRNP prevents R-loop-mediated transcription-replication conflicts and genome instability.

Author information

1
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla-Consejo Superior de Investigaciones Científicas (CSIC), 41092 Seville, Spain;

Abstract

Transcription is a major obstacle for replication fork (RF) progression and a cause of genome instability. Part of this instability is mediated by cotranscriptional R loops, which are believed to increase by suboptimal assembly of the nascent messenger ribonucleoprotein particle (mRNP). However, no clear evidence exists that heterogeneous nuclear RNPs (hnRNPs), the basic mRNP components, prevent R-loop stabilization. Here we show that yeast Npl3, the most abundant RNA-binding hnRNP, prevents R-loop-mediated genome instability. npl3Δ cells show transcription-dependent and R-loop-dependent hyperrecombination and genome-wide replication obstacles as determined by accumulation of the Rrm3 helicase. Such obstacles preferentially occur at long and highly expressed genes, to which Npl3 is preferentially bound in wild-type cells, and are reduced by RNase H1 overexpression. The resulting replication stress confers hypersensitivity to double-strand break-inducing agents. Therefore, our work demonstrates that mRNP factors are critical for genome integrity and opens the option of using them as therapeutic targets in anti-cancer treatment.

KEYWORDS:

DNA damage response; Npl3; R loops; hnRNPs; transcription-associated genome instability; transcription–replication conflicts

PMID:
24240235
PMCID:
PMC3841734
DOI:
10.1101/gad.229880.113
[Indexed for MEDLINE]
Free PMC Article
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