The human nucleoporin Tpr protects cells from RNA-mediated replication stress

Martin Kosar, Michele Giannattasio, Daniele Piccini, Apolinar Maya-Mendoza, Francisco García-Benítez, Jirina Bartkova, Sonia I. Barroso, Hélène Gaillard, Emanuele Martini, Umberto Restuccia, Miguel Angel Ramirez-Otero, Massimiliano Garre, Eleonora Verga, Miguel Andújar-Sánchez, Scott Maynard, Zdenek Hodny, Vincenzo Costanzo, Amit Kumar, Angela Bachi, Andrés Aguilera (), Jiri Bartek () and Marco Foiani ()
Additional contact information
Martin Kosar: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Michele Giannattasio: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Daniele Piccini: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Apolinar Maya-Mendoza: Danish Cancer Society Research Center
Francisco García-Benítez: Universidad de Sevilla-CSIC
Jirina Bartkova: Danish Cancer Society Research Center
Sonia I. Barroso: Universidad de Sevilla-CSIC
Hélène Gaillard: Universidad de Sevilla-CSIC
Emanuele Martini: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Umberto Restuccia: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Miguel Angel Ramirez-Otero: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Massimiliano Garre: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Eleonora Verga: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Miguel Andújar-Sánchez: Complejo Hospitalario Universitario Insular Materno Infantil
Scott Maynard: Danish Cancer Society Research Center
Zdenek Hodny: Institute of Molecular Genetics of the Czech Academy of Sciences
Vincenzo Costanzo: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Amit Kumar: CSIR-Indian Institute of Toxicology Research
Angela Bachi: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Andrés Aguilera: Universidad de Sevilla-CSIC
Jiri Bartek: Institute of Molecular Genetics of the Czech Academy of Sciences
Marco Foiani: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24224-3

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