title: The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress.
abstract: The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Petroni
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Sardina
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Heil
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sahún-Roncero
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Colicchia
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Veschi
authors.affiliation: Paediatric Haematology/Oncology Department, IRCCS, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Albini
authors.affiliation: Paediatric Haematology/Oncology Department, IRCCS, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Fruci
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Ricci
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Soriani
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Deptartment of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Giannini
mesh_terms: D017766:Acid Anhydride Hydrolases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000076228:MRE11 Homologue Protein; D000071447:N-Myc Proto-Oncogene Protein; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; C112156:NBN protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes