Functional interactions between the MRN complex

Area 3: Molecular Genetics of Eukariotes
Functional interactions between the MRN complex and N-Myc in
neuronal development and carcinogenesis
Giuseppe Giannini
Department of Molecular Medicine
: 0039 39 0649255136 - @: [email protected]
Genome integrity needs to be thoroughly preserved for the propagation of genetic
information to subsequent generations. Indeed, inactivation of proteins involved in DNA
damage responses are strictly associated with cancer and/or developmental disorders of
the nervous system. The Nijmegen Breakage syndrome (NBS) due to NBS1 gene
mutations is characterized by microcephaly, facial dysmorphisms and cancer
predisposition. With MRE11 and RAD50, NBS1 forms the MRN-complex, a pivotal
regulator of DNA double strand break repair, whose role in replication stress is also
emerging. Interestingly, microcephaly is also a feature of N-Myc haploinsufficiency in the
human Feingold syndrome. Microcephaly and strongly impaired cerebellar development
with proliferation defects of the granule cell precursors (GCPs) are shared by the CNSrestricted N-Myc and NBS1 KO mice. We have now shown that N-Myc transcriptionally
regulates the MRN complex and requires it to restrain replication stress associated with
the expansion of primary GCPs. Based on these and other preliminar observations, we
raise the hypothesis that N-Myc and the MRN complex are linked in a feedforward circuit
essential for a safe expansion of specific neuronal cell compartmens, but also for N-Mycassociated cancer, such as neuroblastoma and medulloblastoma. Therefore, we designed
a number of approaches based on animal and cellular models already developed in our
laboratory to characterize the biological relevance and the molecular mechanisns of NMyc-MRN interplay. Hopefully our work will shed light on the yet unexplained neuronal
phenotypes of DDR-defective syndromes such as NBS, and potentially provide a proof of
concept for new therapeutic approaches to neuroblastoma and medulloblastoma.
Relevant publications:
1. Veschi V, Petroni M, Bartolazzi A, Altavista P, Dominici C, Capalbo C, Boldrini R,
Castellano A, McDowell HP, Pizer B, Frati L, Screpanti I, Gulino A and Giannini G.
Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in
neuroblastic tumors. Cell Death and Disease. 2014, 5, e1100;
doi:10.1038/cddis.2014.68 Published online 6 March 2014. (IF 5.177)
2. Mazzà D, Infante P, Colicchia V, Greco A, Alfonsi R, Siler M, Antonucci L, Po A, De
Smaele E, Ferretti E, Capalbo C, Bellavia D, Canettieri G, Giannini G, Screpanti I, Gulino
A, Di Marcotullio L. PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53dependent response to genotoxic stress. Cell Death and Differentiation.
2013 Dec;20(12):1688-97. doi: 10.1038/cdd.2013.120. (IF 8.385)
3. Bojesen SE, Pooley KA, Johnatty SE,……..Giannini G., ………Easton DF, Berchuck A,
Antoniou AC, Chenevix- Trench G, Dunning AM. Multiple independent variants at the
TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Nature Genetics. 2013 Apr;45(4):371-84. (IF 29.648)
4. Veschi V, Petroni M, Cardinali B, Dominici C, Screpanti I, Frati L, Bartolazzi A, Gulino A,
Giannini G. Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is
Antagonized by Nutlin-3 in Neuroblastoma Cells. PLoS One. 2012; 7(11):e49139. doi:
10.1371/journal.pone.0049139. Epub 2012 Nov 9. (IF 3.534)
5. Petroni M, Veschi V, Gulino A, Giannini G. Molecular mechanisms of MYCN-dependent
apoptosis and the MDM2p53 pathway: an Achille's heel to be exploited for the therapy of MYCN-amplified
neuroblastoma. Frontiers in Oncology. 2012; 2:141. doi: 10.3389/fonc.2012.00141. (IF to
be defined)
6. Orr N, Lemnrau A, Cooke R, Fletcher O, Tomczyk K, Jones M, Johnson N, Lord CJ,
Mitsopoulos C, Zvelebil M,
McDade SS, Buck G, Blancher C; KConFab Consortium, Trainer AH, James PA, Bojesen
SE, Bokmand S, Nevanlinna H, Mattson J, Friedman E, Laitman Y, Palli D, Masala G,
Zanna I, Ottini L, Giannini G, Hollestelle A, Ouweland AM, Novaković S, Krajc M, GagoDominguez M, Castelao JE, Olsson H, Hedenfalk I, Easton DF, Pharoah PD, Dunning AM,
Bishop DT, Neuhausen SL, Steele L, Houlston RS, Garcia-Closas M, Ashworth A,
Swerdlow AJ. Genome-wide association study identifies a common variant in RAD51B
associated with male breast cancer risk. Nature Genetics. 2012 Sep 23;44(11):1182-4.
doi: 10.1038/ng.2417. (IF 29.648)
7. Petroni M, Veschi V, Prodosmo A, Rinaldo C, Massimi I, Carbonari M, Dominici C,
McDowell HP, Rinaldi C, Screpanti I, Frati L, Bartolazzi A, Gulino A, Soddu S, Giannini G.
MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA
Damage Response. Molecular Cancer Research. 2011 Jan;9(1):67-77. (IF 4.502)
8. Forloni M, Albini S, Limongi MZ, Cifaldi L, Boldrini R, Nicotra MR, Giannini G, Natali PG,
Giacomini P, Fruci D. NF-{kappa}B, and not MYCN, Regulates MHC Class I and
Endoplasmic Reticulum Aminopeptidases in Human Neuroblastoma Cells. Cancer
Research. 2010 Feb 1;70(3):916-24. (IF 9.284)
9. Evangelisti C, Florian MC, Massimi I, Dominici C, Giannini G, Galardi S, Buè MC,
Massalini S, McDowell HP, Messi E, Gulino A, Farace MG, Ciafrè SA. MiR-128 upregulation inhibits Reelin and DCX expression and reduces neuroblastoma cell motility and
invasiveness. FASEB Journal. 2009 Dec;23(12):4276-87. (IF 5.480)
10. Canettieri G, Coni S, Della Guardia M, Nocerino V, Antonucci L, Di Magno L, Screaton
R, Screpanti I, Giannini G, Gulino A. The coactivator CRTC1 promotes cell
Research Group
Anna Coppa, Researcher
Marialaura Petroni,post doc
Francesca Sardina; Constantin Heil; Valeria Colicchia; Maria Saun Ronchero PhD
students
Massimo Zani; Sergio Ferraro Technicians