Artículo
The human nucleoporin Tpr protects cells from RNA-mediated replication stress
Autor/es | Kosar, Martin
Giannattasio, Michele Piccini, Daniele Maya Mendoza, Apolinar García Benítez, Francisco Bartkova, Jirina Barroso Ceballos, Sonia Inés Gaillard, Hélène Martini, Emanuele Restuccia, Umberto Ramírez Otero, Miguel Ángel Garre, Massimiliano Verga, Eleonora Andújar Sánchez, Miguel Maynard, Scott Hodny, Zdenek Costanzo, Vincenzo Kumar, Amit Bachi, Angela Aguilera López, Andrés Bartek, Jiri Foiani, Marco |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2021 |
Fecha de depósito | 2021-08-30 |
Publicado en |
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Resumen | Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. ... Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery. |
Identificador del proyecto | GACR 19-21325S
ERC2014 AdG669898 TARLOOP BFU2016-75058-P |
Cita | Kosar, M., Giannattasio, M., Piccini, D., Maya Mendoza, A., García Benítez, F., Bartkova, J.,...,Foiani, M. (2021). The human nucleoporin Tpr protects cells from RNA-mediated replication stress. Nature Communications, 12 (1), 3937. |
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