Key words: Genomic/Genetic instability; ATM Gene therapy; Animal models;

Genomic instability is a key event of cancer. To preserve genomic stability cells have developped systems to detect and repair DNA double strand breaks (DSBs).DSBs occur in response to exogenous agents, such as chemoterpeutics and during physiological processes as during normal DNA replication, meiotic recombination and lymphocytes maturation. If DSBs are not promptly repaired can be substrates for aberrant chromosomal translocations, which promote cancer.The focus of our research is to restore the function of ATM (Ataxia Telangiectasia Mutated) kinase that through an elaborate signal transduction system, has been established as a central player in DNA DSBs repair and genomic integrity preservation.

Ataxia Telangiectasia (A-T) is an inherited disease caused by a fault in the ATM gene that ultimately leads to death before the forties. The disease affects several body systems and causes neurodegeneration, immunodeficiency, sterility, radiosensitivity, lymphomas and leukemia predisposition. Moreover, missense mutations in ATM kinase domain are also found in many type of cancers, such as leukemia, lymphomas, breast, pancreas and gastric cancers but their impact on ATM function and implications for cancer therapy are largely unknown.

We aim to insert a correct version of ATM gene by lentiviral transduction and to edit ATM point mutations by the CRISPR/CAS9 strategy in human A-T cell lines and hematopoietic progenitor cells of ATM defective mouse models. Re-establishing ATM expression, we expect the rescue of immunological defects and the delay/prevention of thymoma in ATM deficient mice. Moreover, we expect to understand the specific role of ATM kinase activity and its essential targets indispensable for genomic stability maintenance.

Education

• Oct 2011-Sep 2012 postdoctoral position –in cardiovascular field at Sapienza University, Rome, Italy.
• Jun 2007-Jun 2011 postdoctoral position –in Microgravity, germ cells, DNA damage field at Sapienza University, Rome, Italy.
• Jun 2004-May 2007 visiting fellowship Post doc position – in genomic stability and DNA repair field at NCI-NIH, Bethesda, MD, USA.
• Nov 2003-May 2004 Assegno di ricerca –spermatogenesis at Tor Vergata University, Rome, Italy.
• Nov 1999-Oct 2003 PhD in Medical Embriology –Spermatogenesis field at Tor Vergata University, Rome, Italy.
• May 1999-Oct 1999 fellowship – cellular biology, toxicology field at Tor Vergata University, Rome, Italy.
• Dec 1996-Mar 1997 fellowship – molecular biology field at Imperial College School, St. Mary’s hospital, London, UK.
• Oct 1991-Oct 1996 Doctor degree in Biological Sciences – Biochemistry field at University of Perugia, Italy.

Positions

• Apr 2015-Today Researcher with permanent position (Ricercatore III livello) at IBBC-CNR, Monterotondo Scalo, Rome, Italy
• Feb 2014-Feb 2017 PI for a Unit PRIN2012 prot 2012227FLF at University of Molise, Campobasso, Italy
• Oct 2012-Mar 2015 Fixed-term researcher at University of Molise, Campobasso, Italy
• Nov 2009-Nov 2012 PI MFG8904 at Tor Vergata University, Rome, Italy.
• Oct 2011-Oct 2012 Teaching Histology and Embriology as Expert of the subject at University of Molise, Campobasso, Italy

Honours/Awards:

• 01 Sep 2006 NIH FARE Award” “Autophosphorylation at Serine 1987 is dispensable for murine Atm activation in vivo”.
• Dec 1996: Leonardo da Vinci Award for working on the ornitine transcarbamilase gene in Cystic Fibrosis.
• Matriculation with Honour in Biological Sciences at the University of Perugia with a thesis title: “A zinc ion-dependent p-nitrophenylphosphatase from bovine liver: purification, characterization and preparation of an antiserum”. 

Tassinari V, De Gennaro V, La Sala G, Marazziti D, Bolasco G, Aguanno S, De Angelis L, Naro F, Pellegrini M. Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of Ataxia Telangiectasia mouse model. J Cell Sci. 2019 Feb 11. pii: jcs.223008.

Di Siena S, Campolo F, Gimmelli R, Di Pietro C, Marazziti D, Dolci S, Lenzi A, Nussenzweig A, Pellegrini M. Atm reactivation reverses ataxia telangiectasia phenotypes in vivo. Cell Death Dis. 2018 Feb 22;9(3):314.

Daniel JA, Pellegrini M, Lee BS, Guo Z, Filsuf D, Belkina NV, You Z, Paull TT, Sleckman BP, Feigenbaum L, Nussenzweig A. Loss of ATM kinase activity leads to embryonic lethality in mice.J Cell Biol. 2012 Aug 6;198(3):295-304.

Callén E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M and Nussenzweig A. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes.
Cell. 2007 Jul 13;130(1):63-75. IF 31.15

Pellegrini M, Celeste A, Difilippantonio S, Guo R, Wang W, Feigenbaum L and Nussenzweig A. Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature. 2006 Sep 14;443(7108):222-5.

38 Aguanno S, Petrelli C, Di Siena S, De Angelis L, Pellegrini M and Naro F. A Three-Dimensional Culture Model of Reversibly Quiescent Myogenic Cells. Stem Cells International, vol. 2019, Article ID 7548160, 12 pages, 2019. https://doi.org/10.1155/2019/7548160. IF: 4.18

37 Tassinari V, De Gennaro V, La Sala G, Marazziti D, Bolasco G, Aguanno S, De Angelis L, Naro F, Pellegrini M. Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of Ataxia Telangiectasia mouse model. J Cell Sci. 2019 Feb 11. pii: jcs.223008. doi: 10.1242/jcs.223008. IF: 4.4

36 Todaro F, Campolo F, Barrios F, Pellegrini M, Di Cesare S, Tessarollo L, Rossi P, Jannini EA, Dolci S. Regulation of Kit Expression in Early Mouse Embryos and ES Cells. Stem Cells. 2018 Dec 19. doi: 10.1002/stem.2960. IF: 5.5

35 Di Siena S, Campolo F, Gimmelli R, Di Pietro C, Marazziti D, Dolci S, Lenzi A, Nussenzweig A, Pellegrini M. Atm reactivation reverses ataxia telangiectasia phenotypes in vivo. Cell Death Dis. 2018 Feb 22;9(3):314. IF: 5.9

34 Assenza MA, Barbagallo F, Barrios F, Cornacchione M, Campolo F, Vivarelli E, Gianfrilli D, Isidori AM, Lenzi A, Pellegrini M§ and Fabio Naro§. Critical role of Phosphodiesterase 2A in mouse congenital heart defects. Cardiovasc Res. 2018 May 1;114(6):830-845.§ These authors contributed equally to this work IF: 6.2

33 Fassina L, Cornacchione M, Pellegrini M, Mognaschi ME, Gimmelli R, Isidori AM, Lenzi A, Magenes G, Naro F. Model of Murine Ventricular Cardiac Tissue for In Vitro Kinematic-Dynamic Studies of Electromagnetic and β-Adrenergic Stimulation. J Health Eng. 2017;2017:4204085.IF: 0.96

32 Campolo F, Zevini A, Cardarelli S, Monaco L, Barbagallo F, Pellegrini M, Cornacchione M, Di Grazia A, De Arcangelis V, Gianfrilli D, Giorgi M, Lenzi A, Isidori AM, Naro F. Identification of murine Phosphodiesterase 5A isoforms and their functional characterization in HL-1 cardiac cell line. J Cell Physiol. 2018 Jan;233(1):325-337. IF: 4.15

31 Di Siena S, Gimmelli R, Nori SL, Barbagallo F, Campolo F, Dolci S, Rossi P, Venneri MA, Giannetta E, Gianfrilli D, Feigenbaum L, Lenzi A, Naro F, Cianflone E, Mancuso T, Torella D, Isidori AM, Pellegrini M. Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury. Cell Death Dis. 2016 Jul 28; 7(7):e2317. *These authors contributed equally to this work. IF: 5.4

30 Cornacchione M*, Pellegrini M*, Fassina L, Mognaschi ME, Di Siena S, Gimmelli R, Ambrosino P, Soldovieri MV, Taglialatela M, Gianfrilli D, Isidori AM, Lenzi A, Naro F. β- Adrenergic response is counteracted by extremely-low-frequency pulsed electromagnetic fields in beating cardiomyocytes. J Mol Cell Cardiol. 2016; 98:146-58. *These authors contributed equally to this work. IF: 4.8

29 Faieta M, Di Cecca S, de Rooij DG, Luchetti A, Murdocca M, Di Giacomo M, Di Siena S, Pellegrini M, Rossi P, Barchi M. A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11. Chromosoma. 2015; 125(2):189-203. IF: 4.5.

28 Venneri MA, Giannetta E, Panio G, De Gaetano R, Gianfrilli D, Pofi R, Masciarelli S, Fazi F, Pellegrini M, Lenzi A, Naro F, Isidori AM. Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice. PLoS One. 2015 May 11;10(5): e0126580. IF: 3.5.

27 Isidori AM, Cornacchione M, Barbagallo F, Di Grazia A, Barrios F, Fassina L, Monaco L, Giannetta E, Gianfrilli D, Garofalo S, Zhang X, Chen X, Xiang YK, Lenzi A, Pellegrini M*, Naro F*. Inhibition of type 5 phosphodiesterase counteracts β2-Adrenergic signalling in beating cardiomyocytes. Cardiovasc Res. 2015 Jun 1;106(3):408-20. *Co-last authors. IF: 6.2

26 Santini S, Stagni V, Giambruno R, Fianco G, Di Benedetto A, Mottolese M, Pellegrini M and Barilà D. ATM kinase activity modulates ITCH E3-ubiquitin ligase activity.
Oncogene. 2014 Feb 27;33(9):1113-23. IF:6.37

25 Campolo F, Gori M, Favaro R, Nicolis S, Pellegrini M, Botti S, Rossi P, Jannini EA, Dolci S. Essential role of sox2 for the establishment and maintenance of the germ cell line. Stem Cells. 2013 Jul; 31(7):1408-21. IF: 7.78

24 Di Siena S, Campolo F, Jannini EA, Dolci S and Pellegrini M. Genotoxic stress induced by UV and chemotherapy drugs induces ATR relocalization in mouse pachytene spermatocytes. Int J Dev Biol. 2013;57(2-4):281-7 IF:1.9

23 Daniel JA, Pellegrini M, Lee BS, Guo Z, Filsuf D, Belkina NV, You Z, Paull TT, Sleckman BP, Feigenbaum L, Nussenzweig A. Loss of ATM kinase activity leads to embryonic lethality in mice.
J Cell Biol. 2012 Aug 6;198(3):295-304. IF 9.5

22 Barrios F, Filipponi D, Campolo F, Gori M, Bramucci F, Pellegrini M, Ottolenghi S, Rossi P, Jannini EA, Dolci S. SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development. J Cell Sci. 2012 Mar 15;125(Pt 6):1455-64. IF 6.14

21 Langer HF, Orlova VV, Xie C, Kaul S, Schneider D, Lonsdorf AS, Choi EY, Dutoit V, Pellegrini M, Nawroth PP, Santoso S, HwangST, Arnold B, and Chavakis T. A novel function of Junctional Adhesion Molecule-C in mediating melanoma cell metastasis
Cancer Res. 2011 Jun 15;71(12):4096-105. IF 7.54

20 Pellegrini M*, Claps G, Orlova VV, Barrios F, Dolci S, Geremia R, Rossi P, Rossi G, Arnold B, Chavakis T, Feigenbaum L, Sharan SK, Nussenzweig A. Targeted Jam-C deletion in germ cells by Spo11-Cre recombinase. J Cell Sci. 2011 Jan 1; 124(Pt 1):91-9. *Corresponding author IF 6.14

19 Pellegrini M, Di Siena S, Claps G, Di Cesare S, Dolci S, Rossi P, Geremia R and Grimaldi P. Microgravity Promotes Differentiation and Meiotic Entry of Postnatal Mouse Male Germ Cells. PLoS ONE. 2010 Feb 4;5(2):e9064. IF 4.35

18 Barrios F, Filipponi D, Pellegrini M, Paronetto MP, Di Siena S, Geremia R, Rossi P, De Felici M, Jannini EA and Dolci S. Opposing effects of RA and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells. J Cell Sci. 2010 Mar 15;123(Pt 6):871-80. IF 6.14

17 Daniel JA*, Pellegrini M*, Lee JH, Paull TT, Feigenbaum L, and Nussenzweig A.
Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo. J Cell Biol. 2008 Dec 1;183(5):777-83. * These authors contributed equally to this work. IF 9.5

16 Pellegrini M, Filipponi D, Gori M, Barrios F, Lolicato F, Grimaldi P, Rossi P, Jannini EA, Geremia R and Dolci S. ATRA and KL promote differentiation toward the meiotic program of male germ cells. Cell Cycle. 2008 Dec 15;7(24): 3878-88. IF 4.08

15 Campagnolo L, Moscatelli I, Pellegrini M, Siracusa G and Stuhlmann H. Expression of EGFL7 in primordial germ cells and in adult ovaries and testes. Gene Expr Patterns. 2008 Jul;8(6):389- 96. IF 2.76

14 Lolicato F, Marino R, Paronetto MP, Pellegrini M, Dolci S, Geremia R and Grimaldi P. Potential role of Nanos3 in maintaining the undifferentiated spermatogonia population. Dev Biol. 2008 Jan 15;313(2):725-38. IF 4.37

13 Callén E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M and Nussenzweig A. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell. 2007 Jul 13;130(1):63-75. IF 31.15

12 Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin BK, Burkett S, Southon E, Pati D, Tessarollo L, West SC, Donovan PJ, Nussenzweig A, and Sharan SK. RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol. 2007 Feb 26;176(5):581-92. IF 9.5

11 Pellegrini M, Celeste A, Difilippantonio S, Guo R, Wang W, Feigenbaum L and Nussenzweig A. Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature. 2006 Sep 14;443(7108):222-5. IF 34.4

10 Dolci S, Belmonte A, Santone R, Giorgi M, Pellegrini M, Carosa E, Piccione E, Lenzi A, Jannini EA. Subcellular localization and regulation of type-1C and type-5 phosphodiesterases. Biochem Biophys Res Commun. 2006 Mar 17;341(3):837-46. IF 2.54

9 Rossi P, Dolci S, Sette C, Capolunghi F, Pellegrini M, Loiarro M, Di Agostino S, Paronetto MP, Grimaldi P, Merico D, Martegani E and Geremia R. Analysis of the gene expression profile of mouse male meiotic germ cells. Gene Expr Patterns. 2004 May;4(3):267-81. IF 2.7

8 Pellegrini M, Grimaldi P, Rossi P, Geremia R and Dolci S. Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis:a potential role in spermatogonia differentiation. J Cell Sci. 2003, 116:3363-72. IF 6.14

7 La Rosa R, Angiolillo A, Guerrero C, Pellegrini M, Rallo L, Besnard G, Bervillé A, Martin A, Baldoni L. A first linkage map of olive (Olea europaea L.) cultivars using RAPD, AFLP, RFLP and SSR markers. Theor Appl Genet. 2003 May;106(7):1273-82. IF 3.36

6 Dolci S, Grimaldi P, Pellegrini M. Molecular biology tools for dissecting sexual behavior. J Endocrinol Invest. 2003;26(3 Suppl):16-9. IF: 1.99

5 Dolci S, Levati L, Pellegrini M, Faraoni I, Graziani G, Di Carlo A and Geremia R.
Stem cell factor activates telomerase in mouse mitotic spermatogonia and in primordial germ cells. J Cell Sci. 2002, 115:1643-9. IF 6.14

4 Dolci S, Pellegrini M, Di Agostino S, Geremia R and Rossi P. Signaling through extracellular signal-regulated kinase is required for spermatogonial proliferative response to Stem Cell Factor. J Biol Chem. 2001, 276:40225-33. IF 5.32

3 Pellegrini M, Panara F, Angiolillo A, Lucentini L, Maras B and Panara F. Structural and immunological similarities between high molecular weight zinc ion-dependent p- nitrophenilphosphatase and fructose-1,6-bisphosphate aldolase from bovine liver. Biochimica and Biophysica Acta. 2001, 1546:226-233. IF 2.95

2 Panara F and Pellegrini M. Low molecular weight acid phosphatase/phosphotyrosyl protein phosphatase in developing chick brain. Partial characterization and levels during development. J Exp Zool. 1999, 284(1):27-34. IF 2.93

1 Panara F, Guiderdone S, Pellegrini M, Zuccaccia C, Contenti S. Acid phosphatase and zinc ion- dependent acid phosphatase expression in normal human liver and in Hep G2 (human hepatocellular carcinoma) cell line. Cytobios. 1998; 94(376):111-9. IF: 0.48

Researchers:

• Sabrina Putti 
  06-90091-333 |  sabrina.putti@cnr.it
• Tiziana Orsini
  06-90091-334 | tiziana.orsini@cnr.it    

PhD student

• Bruna Sabino Pinho de Oliveira
  

2021 Fondo Europeo per lo Sviluppo Regionale- Regione Lazio- Lazioinnova-POR 2014-2020- A0375-2020-36524 SITeG. Strategies to Implement Glioblastoma Therapy”

2019 ANAT (PI). Title: Gene therapy for Ataxia Telangiectasia syndrome. https://www.associazione-at.it/associazione-nazionale-at/ 

2019 IG grant of AIRC, Project Code: 23329 (PI). Title: Gene therapy for Ataxia Telangiectasia syndrome and for cancer-associated ATM kinase mutations. https://www.airc.it/

2012 PRIN MIUR, Project code: 2012227FLF (Unit). Title: MUSKENDO https://prin.miur.it

2009 MFG grant of AIRC, Project code: 8904 (PI). Title: Relationship between DNA damage and signalling revealed in mouse model of Ataxia Telangiectasia. https://www.airc.it/