Abstract
Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1 i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1 i/i MEFs, together with an increase in heterochromatin- associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogeneinduced senescence, and H-Ras V12-dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.
| Original language | English |
|---|---|
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 108 |
| Issue number | 29 |
| DOIs | |
| Publication status | Published - Jul 19 2011 |
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Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability. / Iotti, Giorgio; Longobardi, Elena; Masella, Silvia; Dardaei, Leila; De Santis, Francesca; Micali, Nicola; Blasi, Francesco.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 29, 19.07.2011.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability
AU - Iotti, Giorgio
AU - Longobardi, Elena
AU - Masella, Silvia
AU - Dardaei, Leila
AU - De Santis, Francesca
AU - Micali, Nicola
AU - Blasi, Francesco
PY - 2011/7/19
Y1 - 2011/7/19
N2 - Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1 i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1 i/i MEFs, together with an increase in heterochromatin- associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogeneinduced senescence, and H-Ras V12-dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.
AB - Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1 i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1 i/i MEFs, together with an increase in heterochromatin- associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogeneinduced senescence, and H-Ras V12-dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.
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UR - http://www.scopus.com/inward/citedby.url?scp=79961068871&partnerID=8YFLogxK
U2 - 10.1073/pnas.1105216108
DO - 10.1073/pnas.1105216108
M3 - Article
C2 - 21715654
AN - SCOPUS:79961068871
VL - 108
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 29
ER -