Institut NeuroMyoGène
    Laboratoire Physiopathologie et Génétique du Neurone et du Muscle
    CNRS UMR 5261 -INSERM U1315
    Université de Lyon - Université Claude Bernard Lyon 1
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GIGLIA-MARIGIGLIA-MARIGIGLIA-MARIGIGLIA-MARI
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EXCISION REPAIR AT THE CROSSROADS WITH TRANSCRIPTION

Cells are the units of organic life and store in their nuclei what constitutes the instruction manual for proper cellular functioning, the DNA molecule. Despite the protection offered by the cellular environment, the integrity of DNA is continuously challenged by a variety of endogenous and exogenous agents (e.g. ultraviolet light, cigarette smoke, environmental pollution, oxidative damage, etc …) that cause DNA lesions, interfering with proper cellular functions, such as transcription, inducing premature cellular death and finally premature ageing and organs dysfunctions. Fortunately, cells have developed counteracting strategies that will repair DNA lesions, preserving the genetic information and the proper cellular functions.

Our team is particularly interested in understanding how DNA repair functions in vivo, in neurons and muscles, and how the transcriptional function is properly restored.

DNA damage Nucleotide Excision Repair Base Excision Repair Cockayne syndrome RNA Polymerase I RNA polymerase II Neurons Chromatin Dynamics
TEAM
  • Ambra GIGLIA-MARI
    SENIOR RESEARCHER CNRS, HDR
  • Pierre-Olivier MARI
    RESEARCHER CNRS
  • Lise-Marie DONNIO
    POST-DOC
  • Charlène MAGNANI
    RESEARCH ASSISTANT UCBL
  • Phoebe RASSINOUX
    RESEARCH ASSISTANT UCBL
  • Shaqraa MUSAWI
    PHD STUDENT
  • Jianbo HUANG
    PHD STUDENT
  • Zehui ZHAO
    PHD STUDENT
FORMER MEMBERS
  • Damien NEUILLET
    RESEARCH ASSISTANT UCBL
  • Florent TAUPELET
    PHD STUDENT

Projects
Publications
Funding
Contact
Directory

 


PROJECTS

DNA REPAIR AND TRANSCRIPTION IN LIVING ORGANISMS

In order to allow the analysis of DNA repair and Transcription in living tissues, we have generated two new model systems, a knock-in mouse model (Xpby/y) expressing a fluorescently tagged TFIIH subunit (XPB) to study NER and Transcription and a knock-in mouse model (Fen1y/y) expressing a fluorescently tagged Fen-1 (Flap-endonuclease-1) to study BER and Replication. Both fluorescent proteins are fully functional and both models are bona fide source of knowledge on the spatio-temporal properties of DNA repair in vivo.Thanks to these new model systems, we have pushed live cell analysis and molecular microscopy to an unprecedented level of sophistication, realizing Fluorescence Recovery after Photobleaching (FRAP) analysis, for the very first time, in living mammalian tissues.Our goals for this project are

  1. Study the structure of the chromatin in different post-mitotic cells
  2. Measure the DNA repair performance in somatic cells in their natural microenvironment.
  3. Reconstitute in vitro the chromatin environment found in post-mitotic cells.

 

TRANSCRIPTION RESUMPTION AFTER DNA REPAIR

When DNA lesions are located on a transcribed gene, transcription is blocked at the damaged site and stalled RNAP2 will recruit DNA repair proteins to restore the genetic information via the pathway known as Transcription Coupled Repair (TCR). Repair proteins will excise the damaged DNA and the replication machinery will resynthesize the gap left by the reaction. Once the replication process is completed, transcription is expected to restart to restore proper cellular functions. Despite this important role for maintaining cellular functionality, the mechanism of RNAP2 restart after DNA repair has been poorly studied.Our goals for this project are

  1. Determine which RNAP2 post-translational modifications are strictly required for restart.
  2. Investigate whether kinases are implicated in RNAP2 restart.

 

DNA REPAIR OF RIBOSOMAL DNA

Ribosome biogenesis is the most energetically costly activity of cells, particularly of high-metabolism cells, such as neurons. More than 60% of cellular transcription results from RNAP1. RNAP1 transcription, the first and rate-limiting step of ribosome biogenesis, is specifically dedicated to produce the ribosomal RNAs (rRNA) from the ribosomal DNA (rDNA) located in the nucleolus.
Within DNA Repair, uncharted territories still remain to be explored; repair of rDNA is one of these territories. The need of acquiring knowledge on this field is more and more evident in view of the importance of ribosome biogenesis for cells like neurons and myocytes, which require a high amount of protein production and hence a high amount of ribosomes. More specifically, neurological problems in CS and TTD patients can be due to problems in ribosome biogenesis. We have recently demonstrated that rDNAs are repaired by the TCR machinery and that during this repair reaction, the RNAP1 is displaced at the border of the nucleolus.Our goals for this project are

  1. Determine which known repair proteins contribute to the repair of the rDNA.
  2. Discover new repair proteins that contribute to the repair of the rDNA.
  3. Map in space and time the repositioning of the RNAP1 during DNA repair.
  4. Investigate which proteins control the displacement of the RNAP1.

 


SELECTED PUBLICATIONS
  • XAB2 Dynamics during DNA Damage-Dependent Transcription Inhibition
    Donnio LM, Cerutti E, Magnani C, Neuillet D, Mari PO, Giglia-Mari G.
    BioRxiv
    doi: https://doi.org/10.1101/2021.12.23.473962
  • β-Actin and Nuclear Myosin I are responsible for nucleolar reorganization during DNA Repair
    Cerutti E , Daniel L, Donnio LM, Neuillet D, Magnani C, Mari PO, Giglia-Mari G
    BioRxiV
    doi: https://doi.org/10.1101/646471
  • Active DNA damage eviction by HLTF stimulates nucleotide excision repair.
    van Toorn M, Turkyilmaz Y, Han S, Zhou D, Kim HS, Salas-Armenteros I, Kim M, Akita M, Wienholz F, Raams A, Ryu E, Kang S, Theil AF, Bezstarosti K, Tresini M, Giglia-Mari G, Demmers JA, Schärer OD, Choi JH, Vermeulen W, Marteijn JA.

    Molecular Cell. 2022 Apr 7;82(7):1343-1358.e8.
    doi: 10.1016/j.molcel.2022.02.020.
    PMID: 35271816

  • Cell-type specific concentration regulation of the basal transcription factor TFIIH in XPBy/y mice model.
    Donnio LM, Miquel C, Vermeulen W, Giglia-Mari G, Mari PO.
    Cancer Cell International. 2019 Sep 10;19:237.
    doi: 10.1186/s12935-019-0945-4.
    PMID : 31516394
  • CSB-Dependent Cyclin-Dependent Kinase 9 Degradation and RNA Polymerase II Phosphorylation during Transcription-Coupled Repair.
    Donnio LM, Lagarou A, Sueur G, Mari PO, Giglia-Mari G.
    Molecular and Cellular Bioliolgy. 2019 Mar 1;39(6). pii: e00225-18.
    doi: 10.1128/MCB.00225-18.
    PMID: 30602496
  • Mechanistic insights in transcription-coupled nucleotide excision repair of ribosomal DNA.
    Daniel L, Cerutti E, Donnio LM, Nonnekens J, Carrat C, Zahova S, Mari PO, Giglia-Mari G.
    Proceedings of the National Academy of Sciences U S A.  2018 Jul 17;115(29):E6770-E6779. doi:10.1073/pnas.1716581115.
    PMID: 29967171

 


FUNDING
  • AFM Myoneuralp (2022-2027)
  • INCA (2019-2023)
  • Ligue contre le Cancer (2020-2022)

 

Email

ambra.mari@univ-lyon1.fr

Phone

+33 4 26 68 82 62

Address

Institut NeuroMyoGene (INMG) – Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM)

UCBL – CNRS UMR 5261 – INSERM U1315
Faculté de Médecine et de Pharmacie

3ème étage
8 avenue Rockefeller
69008 LYON


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