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REPAIR OF OXIDATIVE DNA DAMAGE IN VARIOUS CHROMATIN CONTEXT : AN IN VITRO AND LIVE CELL IMAGING APPROACH

Mardi 19 novembre 2019 11:00 - Duree : 1 heure
Lieu : Salle de Conférence de l’IAB - Rond Point de La Chantourne, 38700 La Tronche (arrêt de tram Grand Sablon, ligne B)

Orateur : Hervé MENONI (IAB, Grenoble)

Endogenous and exogenous factors provoke DNA damage. Fortunately, many repair mechanisms exist to ensure that the 104–105 alterations that occur per nuclear genome on a daily basis are virtually all repaired. Among a plethora of different types of DNA lesions, 8-oxo 7,8-dihydroguanine (8-oxoG) is one of the most abundant (≈ 103 to 104) and thought to be involved in a broad spectrum of human pathogenesis related to cancer, aging, and inflammation. The importance of DNA repair processes is illustrated by the severity of several human syndrome caused by deficiency in DNA repair proteins. For instance deficiencies in Cockayne Syndrome Group B Protein (CSB) or Xeroderma Pigmentosum Group C (XPC) genes, is leading to rare inherited recessive diseases, namely Cockayne Syndrome (CS), a progressive degeneration of the nervous system combined to a segmental accelerated aging or Xeroderma Pigmentosum (XP) with dramatic incidence of skin cancer.

The repair of abundant oxidative DNA damage is primarily performed by the Base Excision Repair (BER). BER of 8-oxoG in mammalian cells is initiated by the 8-oxoG-glycosylase 1 (OGG1). In the end of XXth century, the different steps of BER were studied in details on short pieces of naked DNA substrate. However, how BER operates on more physiological substrates such as chromatin was still unclear. To address this challenge, I established new tools and studied the mechanisms of BER by introducing a single 8-oxoG lesion in the DNA of reconstituted positioned nucleosomes using either conventional histone H2A or a histone variant H2A.Bbd, giving a more open structure to the nucleosome. BER was strongly reduced in both types of nucleosomes. An ATP-dependent chromatin remodeler, (e.g. SWI/SNF), was required to stimulate the BER. Our work disclosed that initiation of BER by glycosylases cannot overcome the nucleosomal barrier and requires specific chromatin remodeling.

In order to further understand BER mechanisms, I set up a novel technique allowing the specific formation of 8-oxoG in various cellular compartments. This novel live-cell imaging approach revealed a strong and very rapid recruitment of two NER-initiating factors (XPC and CSB) to sites of 8-oxoG in living cells. Interestingly, CSB exhibited different and transcription-dependent kinetics in the two compartments studied (nucleolus and nucleoplasm), suggesting a direct transcription-dependent involvement of CSB in the repair of oxidative lesions associated with different RNA polymerases but not involving other NER proteins. Based on our latest results, we propose a model in which CSB plays a role in facilitating BER progression at transcribed genes, probably to allow XRCC1 (an essential downstream BER factor) recruitment to BER-intermediates masked by RNA polymerase II complexes stalled at these intermediates.

Contact : karin.sadoul@univ-grenoble-alpes.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (IAB)
Nature évènement : (Séminaire)
Evènement répétitif : (Mardis de l’IAB)
Site de l'évènement : Pôle Santé / La Tronche

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