IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Transcriptional upregulation of p19INK4d upon diverse genotoxic stress is critical for optimal DNA damage response
Autor/es:
JULIETA M. CERUTI; MARÍA E. SCASSA; MARIELA C. MARAZITA; ABEL C. CARCAGNO; PABLO F. SIRKIN; EDUARDO T. CÁNEPA
Revista:
INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELLULAR BIOLOGY
Referencias:
Año: 2009 vol. 41 p. 1344 - 1353
ISSN:
1357-2725
Resumen:
p19INK4d promotes survival of several cell lines after UV irradiation due to enhanced DNA repair, independently
of CDK4 inhibition. To further understand the action of p19INK4d in the cellular response
to DNA damage, we aimed to elucidate whether this novel regulator plays a role only in mechanisms
triggered by UV or participates in diverse mechanisms initiated by different genotoxics. We found that
p19INK4d is induced in cells injured with cisplatin or -amyloid peptide as robustly as with UV. The
mentioned genotoxics transcriptionally activate p19INK4d expression as demonstrated by run-on assay
without influencing its mRNA stability and with partial requirement of protein synthesis. It is not currently
known whether DNA damage-inducible genes are turned on by the DNA damage itself or by the
consequences of that damage. Experiments carried out in cells transfected with distinct damaged DNA
structures revealed that the damage itself is not responsible for the observed up-regulation. It is also not
known whether the increased expression of DNA-damage-inducible genes is related to immediate protective
responses such as DNA repair or to more delayed responses such as cell cycle arrest or apoptosis.
We found that ectopic expression of p19INK4d improves DNA repair ability and protects neuroblastoma
cells from apoptosis caused by cisplatin or -amyloid peptide. Using clonal cell lines where p19INK4d
levels can be modified at will, we show that p19INK4d expression correlates with increased survival and
clonogenicity. The results presented here, prompted us to suggest that p19INK4d displays an important
role in an early stage of cellular DNA damage response.