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Excitability and calcium signaling in normal and diseased skeletal muscle

Architecture du noyau et du cytosquelette musculaire

Nucleolar Dynamic Reorganization in action during DNA Repair (Nu-DyRection)

Ambra Giglia-Mari

About

One of the most fascinating and relatively unexplored areas in the field of DNA repair is how cells restore their normal functions after completing the processes that eliminate DNA lesions and re-establish DNA sequence continuity. DNA lesions not only impede transcription, replication, and the cell cycle, but may also disrupt the proper positioning of chromatin domains within the nucleus and alter nucleolar organization.
Our team is focused on the molecular mechanisms involved in the restoration of transcriptional activity, particularly the reorganization of nucleolar structure following DNA damage and repair.

The nucleolus is a membraneless nuclear organelle with a highly structured internal organization. This organization is associated with its various functions in ribosomal biogenesis: transcription of ribosomal DNA (rDNA) by RNA Polymerase 1 (RNAP1) and the early maturation of ribosomal RNA. This highly organized structure can be significantly disrupted by both genotoxic agents and general cellular stress.
In the last years, we have shown that after a genotoxic stress (UV: Ultraviolet irradiation), RNAP1 and nucleolar DNA are exported to the periphery of the nucleolus. Interestingly, proper nucleolar structure is only restored after the complete repair of all the lesions on the nucleolar DNA, both active and inactive regions. In addition to an efficient repair system, the restoration of normal nucleolar structure after DNA repair completion requires the presence of key proteins.
One such protein is SMN (Survival of Motor Neuron), which is altered in patients suffering from Spinal Muscular Atrophy (SMA). We have found that in absence of SMN, RNAP1 remains at the periphery of the nucleolus after DNA damage repair. Unexpectedly, we observed that SMN shuttles from Cajal bodies (CBs) into the nucleolus after the completion of DNA repair, but before the restoration of nucleolar structure. Together with SMN, other proteins, such as Fibrillarin (FBL), Coilin, Nuclear Myosin 1 (NM1), appear to be also important for this process.

Our group has the following objectives:

To investigate the dynamic reorganization of nucleoli following stress
To elucidate the mechanism by which nucleolar homeostasis is restored upon DNA repair completion
To identify the critical factors governing nucleolar homeostasis during and after DNA Repair

Credit: Lise-Marie Donnio

Members

Ambra Giglia-Mari

Candice Benedetti

Manon Courtieux

Engineer assistant

Lise-Marie Donnio

Engineer assistant

Charlène Magnani

Engineer assistant

Pierre-Olivier Mari

Phoebe Rassinoux

Jean-Luc Thomas

Research Engineer

Bilan Charmarke Youssouf

Marilou Chevroton

Luc-Alban Lhoste

Events

men and women sitting on chairs inside room

New insights into physiopathogenetics of Spinal Muscular Atrophy

men and women sitting on chairs inside room

Nucleotide Excision Repair at the crossroad with transcription

The integrity of DNA is continuously challenged by a variety of endogenous and exogenous agents (e.g. ultraviolet light, cigarette smoke, […]

News

Candice Kutchukian awarded the 2018 SBCF PhD Thesis Prize

Candice Kutchukian received the 2018 PhD Thesis Prize from the French Society for Cell Biology.

Publications

Lise‐marie Donnio, Giuseppina Giglia-Mari, Keep calm and reboot – how cells restart transcription after DNA damage and DNA repair, FEBS Lett 2025 Jan; 599(2): 275-294.

Edwige Belotti, Nicolas Lacoste, Arslan Iftikhar, Thomas Simonet, Christophe Papin, Alexis Osseni, N..., H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers, Nucleic Acids Res 2024 Apr; 52(6): 3031-3049.

Haser H Sutcu, Phoebe Rassinoux, Lise-Marie Donnio, Damien Neuillet, François Vianna-Legros, Olivie..., Decline of DNA damage response along with myogenic differentiation, Life Sci Alliance 2024 Feb; 7(2): .

Jérémy Sandoz, Max Cigrang, Amélie Zachayus, Philippe Catez, Lise-Marie Donnio, Clèmence Elly, J..., Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress, Nature Communications.

Shaqraa Musawi, Lise-Marie Donnio, Zehui Zhao, Charlène Magnani, Phoebe Rassinoux, Olivier Binda, J..., Nucleolar reorganization after cellular stress is orchestrated by SMN shuttling between nuclear compartments, Nat Commun 2023 Nov; 14(1): 7384.

Elena Cerutti, Laurianne Daniel, Lise-Marie Donnio, Damien Neuillet, Charlene Magnani, Pierre-Olivie..., β-Actin and Nuclear Myosin I are responsible for nucleolar reorganization during DNA Repair, .

Shaqraa Musawi, Lise-Marie Donnio, Charlène Magnani, Olivier Binda, Jocelyn Côté, Patrick Lomonte..., Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling Between Nuclear Compartments, .

Lise-Marie Donnio, Elena Cerutti, Charlene Magnani, Damien Neuillet, Pierre-Olivier Mari, Giuseppina..., XAB2 dynamics during DNA damage-dependent transcription inhibition, eLife.

Florent Taupelet, Lise-Marie Donnio, Charlène Magnani, Pierre-Olivier Mari, Giuseppina Giglia-Mari, A stable XPG protein is required for proper ribosome biogenesis: Insights on the phenotype of combinate Xeroderma Pigmentosum/Cockayne Syndrome patients, PLoS ONE.

Lise-Marie Donnio, Catherine Miquel, Wim Vermeulen, Giuseppina Giglia-Mari, Pierre-Olivier Mari, Cell-type specific concentration regulation of the basal transcription factor TFIIH in XPBy/y mice model, Cancer Cell International.

Alain Sarasin, Giuseppina Giglia-Mari, p53 gene mutations in human skin cancers., Experimental Dermatology.

Lise-Marie Donnio, Anna Lagarou, Gabrielle Sueur, Pierre-Olivier Mari, Giuseppina Giglia-Mari, CSB-Dependent Cyclin-Dependent Kinase 9 Degradation and RNA Polymerase II Phosphorylation during Transcription-Coupled Repair, Molecular and Cellular Biology.

S. Mourgues, V. Gautier, A. Lagarou, C. Bordier, A. Mourcet, J. Slingerland, L. Kaddoum, Frédéric ..., ELL, a novel TFIIH partner, is involved in transcription restart after DNA repair, Proceedings of the National Academy of Sciences of the United States of America.

Julie Nonnekens, Jorge Perez-Fernandez, Arjan F Theil, Olivier Gadal, Chrystelle Bonnart, Giuseppina..., Mutations in TFIIH causing trichothiodystrophy are responsible for defects in ribosomal RNA production and processing, Human Molecular Genetics.

Marion Maisonobe, Giuseppina Giglia-Mari, Denis Eckert, DNA Repair: A changing geography? (1964–2008), DNA Repair.

Lara Kaddoum, Nicolas Panayotis, Honoré Mazarguil, Giuseppina Giglia-Mari, Jean Christophe Roux, Et..., Isoform-specific anti-MeCP2 antibodies confirm that expression of the e1 isoform strongly predominates in the brain, F1000Research.

Camille Godon, Sophie Mourgues, Julie Nonnekens, Amandine Mourcet, Frédéric Coin, Wim Vermeulen, P..., Generation of DNA single-strand displacement by compromised nucleotide excision repair, The EMBO Journal.

Frédéric Coin, Bernardo Reina-San-Martin, Giuseppina Giglia-Mari, Mark Berneburg, DNA in 3R: Repair, Replication, and Recombination, Biochemistry and molecular biology international.

G. Giglia-Mari, A. Zotter, W. Vermeulen, DNA Damage Response, Cold Spring Harbor Perspectives in Biology.

Overmeer RM, Gourdin AM, Giglia-Mari A, Kool H, Houtsmuller AB, Siegal G, Fousteri MI, Mullenders LH..., Replication factor C recruits DNA polymerase delta to sites of nucleotide excision repair but is not required for PCNA recruitment., Mol Cell Biol 2010 Oct; 30(20): 4828-39.

Giuseppina Giglia-Mari, Arjan F Theil, Pierre-Olivier Mari, Sophie Mourgues, Julie Nonnekens, Lise A..., Differentiation Driven Changes in the Dynamic Organization of Basal Transcription Initiation, PLoS Biology.

Simone Sabbioneda, Audrey Gourdin, Catherine Green, Angelika Zotter, Giuseppina Giglia-Mari, Adriaan..., Effect of Proliferating Cell Nuclear Antigen Ubiquitination and Chromatin Structure on the Dynamic Properties of the Y-family DNA Polymerases, Molecular Biology of the Cell.

Giuseppina Giglia-Mari, Alain Sarasin, TP53 mutations in human skin cancers, Human Mutation.

Alain Spatz, Giuseppina Giglia-Mari, Simone Benhamou, Alain Sarasin, Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum, Cancer Research.