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Título

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

AutorGarcía-Benítez, Francisco; Gaillard, Hélène ; Aguilera, Andrés
Palabras claveGenome instability
R loop
Transcription
Nuclear pores
Mpl1/2
Fecha de publicación2017
EditorNational Academy of Sciences (U.S.)
CitaciónProceedings of the National Academy of Sciences 114(41): 10942-10947 (2017)
ResumenDuring 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 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.
URIhttp://hdl.handle.net/10261/165664
Identificadoresdoi: 10.1073/pnas.1707845114
e-issn: 1091-6490
issn: 0027-8424
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