RT Journal Article
T1 Yra1-bound RNA-DNA hybrids cause orientation-independent transcription-replication collisions and telomere instability.
A1 García-Rubio, María
A1 Aguilera, Paula
A1 Lafuente-Barquero, Juan
A1 Ruiz, José F
A1 Simon, Marie-Noelle
A1 Geli, Vincent
A1 Rondón, Ana G
A1 Aguilera, Andrés
K1 R loop
K1 Yra1
K1 telomeres
K1 transcription–replication collision
AB 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.
YR 2018
FD 2018-06-28
LK http://hdl.handle.net/10668/12656
UL http://hdl.handle.net/10668/12656
LA en
DS RISalud
RD Apr 20, 2025