Artículo
Yra1-bound RNA–DNA hybrids cause orientation-independent transcription– replication collisions and telomere instability
Autor/es | García Rubio, María Luisa
Aguilera, Paula Lafuente Barquero, Juan Ruiz, José F. Simon, Marie-Noelle Geli, Vincent García Rondón, Ana Aguilera López, Andrés |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2018 |
Fecha de depósito | 2018-08-29 |
Publicado en |
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Resumen | R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, ... R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA–DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA– DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription–replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA–DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells. |
Identificador del proyecto | ERC2014 AdG669898 TARLOOP
BFU2016-75058-P PA12- BIO1238 |
Cita | García Rubio, M., Aguilera, P., Lafuente Barquero, J., Ruiz, J.F., Simon, M., Geli, V.,...,Aguilera López, A. (2018). Yra1-bound RNA–DNA hybrids cause orientation-independent transcription– replication collisions and telomere instability. Genes and Development, 32 (13-14), 965-977. |
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