Abstract
Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD+-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development. We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone modifications associated with constitutive heterochromatin integrity.
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References
Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528
Menissier de Murcia J, Ricoul M, Tartier L, Niedergang C, Huber A, Dantzer F, Schreiber V, Ame JC, Dierich A, LeMeur M, Sabatier L, Chambon P, de Murcia G (2003) Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J 22:2255–2263
Quenet D, El Ramy R, Schreiber V, Dantzer F (2009) The role of poly(ADP-ribosyl)ation in epigenetic events. Int J Biochem Cell Biol 41:60–65
Cohen-Armon M, Visochek L, Rozensal D, Kalal A, Geistrikh I, Klein R, Bendetz-Nezer S, Yao Z, Seger R (2007) DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. Mol Cell 25:297–308
Klenova E, Ohlsson R (2005) Poly(ADP-ribosyl)ation and epigenetics. Is CTCF PARt of the plot? Cell Cycle 4:96–101
Poirier GG, de Murcia G, Jongstra-Bilen J, Niedergang C, Mandel P (1982) Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure. Proc Natl Acad Sci USA 79:3423–3427
Rouleau M, Aubin RA, Poirier GG (2004) Poly(ADP-ribosyl)ated chromatin domains: access granted. J Cell Sci 117:815–825
Tulin A, Chinenov Y, Spradling A (2003) Regulation of chromatin structure and gene activity by poly(ADP-ribose) polymerases. Curr Top Dev Biol 56:55–83
Yelamos J, Schreiber V, Dantzer F (2008) Toward specific functions of poly(ADP-ribose) polymerase-2. Trends Mol Med 14:169–178
Dantzer F, Giraud-Panis MJ, Jaco I, Ame JC, Schultz I, Blasco M, Koering CE, Gilson E, Menissier-de Murcia J, de Murcia G, Schreiber V (2004) Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol Cell Biol 24:1595–1607
Beneke S, Cohausz O, Malanga M, Boukamp P, Althaus F, Burkle A (2008) Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1. Nucleic Acids Res 36:6309–6317
Gomez M, Wu J, Schreiber V, Dunlap J, Dantzer F, Wang Y, Liu Y (2006) PARP1 Is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres. Mol Biol Cell 17:1686–1696
O’Connor MS, Safari A, Liu D, Qin J, Songyang Z (2004) The human Rap1 protein complex and modulation of telomere length. J Biol Chem 279:28585–28591
Saxena A, Wong LH, Kalitsis P, Earle E, Shaffer LG, Choo KH (2002) Poly(ADP-ribose) polymerase 2 localizes to mammalian active centromeres and interacts with PARP-1, Cenpa, Cenpb and Bub3, but not Cenpc. Hum Mol Genet 11:2319–2329
Saxena A, Saffery R, Wong LH, Kalitsis P, Choo KH (2002) Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose) polymerase-1 protein and are poly(ADP-ribosyl)ated. J Biol Chem 277:26921–26926
Meder VS, Boeglin M, de Murcia G, Schreiber V (2005) PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. J Cell Sci 118:211–222
Augustin A, Spenlehauer C, Dumond H, Menissier-De Murcia J, Piel M, Schmit AC, Apiou F, Vonesch JL, Kock M, Bornens M, De Murcia G (2003) PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression. J Cell Sci 116:1551–1562
Quenet D, Gasser V, Fouillen L, Cammas F, Sanglier-Cianferani S, Losson R, Dantzer F (2008) The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1beta and the heterochromatin protein HP1alpha. FASEB J 22:3853–3865
Dantzer F, Mark M, Quenet D, Scherthan H, Huber A, Liebe B, Monaco L, Chicheportiche A, Sassone-Corsi P, de Murcia G, Menissier-de Murcia J (2006) Poly(ADP-ribose) polymerase-2 contributes to the fidelity of male meiosis I and spermiogenesis. Proc Natl Acad Sci USA 103:14854–14859
Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73:417–435
Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, Chua KF (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA 100:10794–10799
McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M (2003) The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 23:38–54
Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, Kim S, Xu X, Zheng Y, Chilton B, Jia R, Zheng ZM, Appella E, Wang XW, Ried T, Deng CX (2008) Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14:312–323
Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D (2007) SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450:440–444
Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16:93–105
Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G, Sassone-Corsi P (2006) Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 5:873–877
de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M, Walztinger C, Chambon P, de Murcia G (1997) Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 94:7303–7307
Pennarun G, Granotier C, Hoffschir F, Mandine E, Biard D, Gauthier LR, Boussin FD (2008) Role of ATM in the telomere response to the G-quadruplex ligand 360A. Nucleic Acids Res 36:1741–1754
Kolthur-Seetharam U, Teerds K, de Rooij DG, Wendling O, McBurney M, Sassone-Corsi P, Davidson I (2009) The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic-pituitary gonadotropin signaling. Biol Reprod 80:384–391
Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D (2006) SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 20:1256–1261
Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, Weipoltshammer K, Pagani M, Lachner M, Kohlmaier A, Opravil S, Doyle M, Sibilia M, Jenuwein T (2001) Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107:323–337
Shav-Tal Y, Blechman J, Darzacq X, Montagna C, Dye BT, Patton JG, Singer RH, Zipori D (2005) Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition. Mol Biol Cell 16:2395–2413
Espada J, Ballestar E, Santoro R, Fraga MF, Villar-Garea A, Nemeth A, Lopez-Serra L, Ropero S, Aranda A, Orozco H, Moreno V, Juarranz A, Stockert JC, Langst G, Grummt I, Bickmore W, Esteller M (2007) Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells. Nucleic Acids Res 35:2191–2198
Peng JC, Karpen GH (2007) H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat Cell Biol 9:25–35
Chen T, Hevi S, Gay F, Tsujimoto N, He T, Zhang B, Ueda Y, Li E (2007) Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat Genet 39:391–396
Trucco C, Oliver FJ, de Murcia G, Menissier-de Murcia J (1998) DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines. Nucleic Acids Res 26:2644–2649
Kanai M, Tong WM, Sugihara E, Wang ZQ, Fukasawa K, Miwa M (2003) Involvement of poly(ADP-Ribose) polymerase 1 and poly(ADP-Ribosyl)ation in regulation of centrosome function. Mol Cell Biol 23:2451–2462
Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100:1512–1521
Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J (2004) Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95:971–980
Pillai JB, Isbatan A, Imai S, Gupta MP (2005) Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+depletion and reduced Sir2alpha deacetylase activity. J Biol Chem 280:43121–43130
Pillai JB, Gupta M, Rajamohan SB, Lang R, Raman J, Gupta MP (2006) Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 291:H1545–1553
Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907–918
Denu JM (2003) Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases. Trends Biochem Sci 28:41–48
Zhang R, Liu ST, Chen W, Bonner M, Pehrson J, Yen TJ, Adams PD (2007) HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells. Mol Cell Biol 27:949–962
Stevens FE, Beamish H, Warrener R, Gabrielli B (2008) Histone deacetylase inhibitors induce mitotic slippage. Oncogene 27:1345–1354
Hassa PO, Haenni SS, Buerki C, Meier NI, Lane WS, Owen H, Gersbach M, Imhof R, Hottiger MO (2005) Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem 280:40450–40464
Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Konstatin B, Samant S, Hottiger MO, Gupta MP (2009) SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly (ADP-ribose) polymerase 1. Mol Cell Biol. [Epub ahead of print]
Dantzer F, de La Rubia G, Menissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V (2000) Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry 39:7559–7569
Acknowledgments
We thank G. de Murcia and J.C. Amé for helpful discussions. This work was supported by funds from Centre National de la Recherche Scientifique, Université de Strasbourg, Agence Nationale de la Recherche and Ligue Nationale Contre le Cancer, Comité du Bas-Rhin.
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Sup.Fig.1. Retarded growth of Parp-1;SirT1 double knockout mice. Average weight curves of Parp-1+/+;SirT1+/+ (◆), Parp-1+/−;SirT1+/− (◊), Parp-1+/+;SirT1−/− (●), Parp-1+/−;SirT1−/− (▲) and Parp-1−/−;SirT1−/− (×) females (left panel) and males (right panel) ; n, number of mice included in the weigth curves. Parp-1−/−;SirT1−/− mice were 30-40% smaller compared to controls. For the female, this represents an exacerbation of the 20-30% reduction seen in Parp-1+/+; SirT1−/− mice (this study and (McBurney, M.W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J.R., Lansdorp, P.M. and Lemieux, M. (2003). The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 23, 38-54.)). (PPT 206 kb)
Sup.Fig.2
(A) Normal patterns of H3K9me3 and HP1α in Parp-1-deficient cells. Representative immunofluorescence images for the comparative distribution of H3K9me3 (b,c) and HP1α (f,h) in Parp-1+/+;SirT1+/+ (a,b,e,f) and Parp-1−/−;SirT1+/+ (c,d,g,h) interphase cells. DNA and heterochromatic foci are counterstained with DAPI (a,c,e,g). Scale bars, 4,45 μm. (B) Dispersed distribution of H3K9me3 in Parp-1−/−;SirT1−/− cells reconstituted with Parp-1. Parp-1−/− ;SirT1−/− cells were transfected with either EGFP-Parp-1 or GST-Parp-1 and processed for immunofluorescence 36h later. a,d: DAPI-stained DNA. b: EGFP fluorescence. e: green labeled anti-GST antibody. c,f: red labeled anti anti-H3K9me3 antibody. Scale bars, 11 μm. (PPT 4483 kb)
Sup.Fig.3
Western-blot analysis for the expression of SirT1 and β-actin in SirT1-transfected cells. Equivalent amounts of total protein extracts from mock-transfected (lanes 1,3) or pCruz-HA-SirT1 transfected (lanes 2,4) Parp-1+/+;SirT1+/+ (lanes 1-2) and Parp-1+/+;SirT1−/− (lanes 3-4) 3T3 cells were separated by SDS-PAGE and analyzed by Western blotting with the appropriate antibodies. (PPT 80 kb)
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El Ramy, R., Magroun, N., Messadecq, N. et al. Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes. Cell. Mol. Life Sci. 66, 3219–3234 (2009). https://doi.org/10.1007/s00018-009-0105-4
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DOI: https://doi.org/10.1007/s00018-009-0105-4