The human nucleoporin Tpr protects cells from RNA-mediated replication stress.
Acetyltransferases
/ genetics
Cell Survival
DNA Damage
DNA Replication
Genomic Instability
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Neoplasms
/ genetics
Nuclear Pore Complex Proteins
/ genetics
Protein Interaction Maps
Proto-Oncogene Proteins
/ genetics
RNA Transport
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 06 2021
24 06 2021
Historique:
received:
17
08
2020
accepted:
04
06
2021
entrez:
25
6
2021
pubmed:
26
6
2021
medline:
13
7
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34168151
doi: 10.1038/s41467-021-24224-3
pii: 10.1038/s41467-021-24224-3
pmc: PMC8225803
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Nuclear Pore Complex Proteins
0
Proto-Oncogene Proteins
0
TPR protein, human
0
Acetyltransferases
EC 2.3.1.-
MCM3AP protein, human
EC 2.3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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