Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability
|Author/s||García Benítez, Francisco
Aguilera López, Andrés
Universidad de Sevilla. Departamento de Ingeniería y Ciencia de los Materiales y del Transporte
|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 ...
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.
|Funding agencies||European Research Council (ERC)
Ministerio de Economía y Competitividad (MINECO). España
European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Ministerio de Educación, Cultura y Deporte (MECD). España
|Project ID.||ERC2014 AdG669898 TARLOOP
|Citation||García Benítez, F., Gaillard, H. y Aguilera López, A. (2017). Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability. Proceedings of the National Academy of Sciences, 114 (41), 10942-10947.|