Advanced

Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita

Bellodi, Cristian LU ; Kopmar, Noam and Ruggero, Davide (2010) In EMBO Journal 29(11). p.76-1865
Abstract

Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap- and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5'untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1(m)... (More)

Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap- and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5'untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1(m) cells, p53 IRES-dependent translation is impaired during OIS ex vivo and on DNA damage in vivo. This defect in p53 translation perturbs the cellular response that counteracts oncogenic insult. We extend these findings to X-DC human patient cells in which similar impairments in p53 IRES-dependent translation are observed. Importantly, re-introduction of wild-type DKC1 restores p53 expression in these cells. These results provide insight into the basis for cancer susceptibility in human syndromes associated with ribosome dysfunction.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aging, DNA Damage, Dyskeratosis Congenita, Genes, p53, Humans, Oncogenes, RNA, Ribosomal, Ribosomes, Tumor Suppressor Protein p53, Untranslated Regions
in
EMBO Journal
volume
29
issue
11
pages
12 pages
publisher
Oxford University Press
external identifiers
  • Scopus:77953122619
ISSN
1460-2075
DOI
10.1038/emboj.2010.83
language
English
LU publication?
no
id
b33475dd-993b-462c-9394-7e68d6ce9383
date added to LUP
2016-04-29 15:54:48
date last changed
2016-11-27 04:39:52
@misc{b33475dd-993b-462c-9394-7e68d6ce9383,
  abstract     = {<p>Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap- and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5'untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1(m) cells, p53 IRES-dependent translation is impaired during OIS ex vivo and on DNA damage in vivo. This defect in p53 translation perturbs the cellular response that counteracts oncogenic insult. We extend these findings to X-DC human patient cells in which similar impairments in p53 IRES-dependent translation are observed. Importantly, re-introduction of wild-type DKC1 restores p53 expression in these cells. These results provide insight into the basis for cancer susceptibility in human syndromes associated with ribosome dysfunction.</p>},
  author       = {Bellodi, Cristian and Kopmar, Noam and Ruggero, Davide},
  issn         = {1460-2075},
  keyword      = {Aging,DNA Damage,Dyskeratosis Congenita,Genes, p53,Humans,Oncogenes,RNA, Ribosomal,Ribosomes,Tumor Suppressor Protein p53,Untranslated Regions},
  language     = {eng},
  month        = {06},
  number       = {11},
  pages        = {76--1865},
  publisher    = {ARRAY(0xb576350)},
  series       = {EMBO Journal},
  title        = {Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita},
  url          = {http://dx.doi.org/10.1038/emboj.2010.83},
  volume       = {29},
  year         = {2010},
}