RT Journal Article
T1 The human nucleoporin Tpr protects cells from RNA-mediated replication stress.
A1 Kosar, Martin
A1 Giannattasio, Michele
A1 Piccini, Daniele
A1 Maya-Mendoza, Apolinar
A1 García-Benítez, Francisco
A1 Bartkova, Jirina
A1 Barroso, Sonia I
A1 Gaillard, Hélène
A1 Martini, Emanuele
A1 Restuccia, Umberto
A1 Ramirez-Otero, Miguel Angel
A1 Garre, Massimiliano
A1 Verga, Eleonora
A1 Andújar-Sánchez, Miguel
A1 Maynard, Scott
A1 Hodny, Zdenek
A1 Costanzo, Vincenzo
A1 Kumar, Amit
A1 Bachi, Angela
A1 Aguilera, Andrés
A1 Bartek, Jiri
A1 Foiani, Marco
AB 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.
YR 2021
FD 2021-06-24
LK http://hdl.handle.net/10668/18040
UL http://hdl.handle.net/10668/18040
LA en
DS RISalud
RD Apr 12, 2025