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Molecular and Cellular Biology, April 2009, p. 1989-1998, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.00552-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

hSirT1-Dependent Regulation of the PCAF-E2F1-p73 Apoptotic Pathway in Response to DNA Damage{triangledown}

Natalia Pediconi,1,2,{dagger} Francesca Guerrieri,3,5,{dagger} Stefania Vossio,1,3 Tiziana Bruno,2 Laura Belloni,1,4 Valeria Schinzari,3 Cecilia Scisciani,1,2 Maurizio Fanciulli,2 and Massimo Levrero1,2,3,4,5*

Laboratory of Gene Expression, Fondazione A Cesalpino, Viale del Policlinico 155, 00161 Rome, Italy,1 Rome Oncogenomic Center, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy,2 INSERM U785/Sapienza Università, Viale del Policlinico 155, 00161 Rome, Italy,3 Fondazione Cenci Bolognetti/Istituto Pasteur, Sapienza Università, Viale del Policlinico 155, 00161 Rome, Italy,4 Department of Internal Medicine, Sapienza Università, Viale del Policlinico 155, 00161 Rome, Italy5

Received 5 April 2008/ Returned for modification 7 July 2008/ Accepted 24 November 2008

The NAD+-dependent histone deacetylase hSirT1 regulates cell survival and stress responses by inhibiting p53-, NF-{kappa}B-, and E2F1-dependent transcription. Here we show that the hSirT1/PCAF interaction controls the E2F1/p73 apoptotic pathway. hSirT1 represses E2F1-dependent P1p73 promoter activity in untreated cells and inhibits its activation in response to DNA damage. hSirT1, PCAF, and E2F1 are corecruited in vivo on theP1p73 promoter. hSirT1 deacetylates PCAF in vitro and modulates PCAF acetylation in vivo. In cells exposed to apoptotic DNA damage, nuclear NAD+ levels decrease and inactivate hSirT1 without altering the hSirT1 interaction with PCAF and hSirT1 binding to the P1p73 promoter. The reactivation of hSirT1 by pyruvate that increases the [NAD+]/[NADH] ratio completely abolished the DNA damage-induced activation of TAp73 expression, thus linking the modulation of chromatin-bound hSirT1 deacetylase activity by the intracellular redox state with P1p73 promoter activity. The release of PCAF from hSirT1 repression favors the assembly of transcriptionally active PCAF/E2F1 complexes onto the P1p73 promoter and p53-independent apoptosis. Our results identify hSirT1 and PCAF as potential targets to modulate tumor cell survival and chemoresistance irrespective of p53 status.

* Corresponding author. Mailing address: Department of Internal Medicine, Sapienza Università, Viale del Policlinico 155, 00161 Rome, Italy. Phone: 39.06.5266.2601. Fax: 39.06.4938.3333. E-mail: Massimo.levrero{at}uniroma1.it

{triangledown} Published ahead of print on 2 February 2009.

{dagger} N.P. and F.G. are joint first authors.

Molecular and Cellular Biology, April 2009, p. 1989-1998, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.00552-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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