Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
Our group has identified several transcription factors that function as auxiliary factors in base excision repair. Interestingly, some of these auxiliary factors are overexpressed in specific cancers where their function is essential to the survival of cancer cells. Moreover, because these factors stimulate the enzymatic activities of DNA repair enzymes, they increase the resistance of cancer cells to genotoxic treatments such as radiotherapy and many chemotherapeutic agents. Expression knockdown of these factors is synthetic lethal to cancer cells, while causing no harm to normal cells. This is in contrast to DNA repair enzymes which are essential to normal cells. Thus, DNA repair auxiliary factors represent potential therapeutic targets.
We perform structure/function analysis of auxiliary factors using in vitro and in vivo assays; we perform DNA repair assays with purified proteins and cell extracts; following gene knockdown or knockout and overexpression of recombinant proteins in cells, we measure various types of DNA damage, we monitor DNA repair efficiency and evaluate the resistance of cancer cells to ionizing radiation and various chemotherapeutic agents. Also, since auxiliary factors are required for cancer cells to avoid cellular senescence in the presence of a RAS oncogene, we perform transformation and cooperation assays in tissue culture and transgenic mice.
What we are
currently
working on
Dr. Nepveu’s laboratory studies the regulation of transcription in mammalian cells and, in particular, the roles of transcription factors in DNA damage responses. We combine a vast array of molecular biology and functional genomic approaches together with tissue culture and mouse models to investigate how alterations in DNA repair and DNA damage responses contribute to the initiation and progression of cancer. We study how defects in DNA repair can contribute to tumor initiation and how certain cancer cells become dependent on specific DNA repair pathways. It is generally accepted that defects in DNA repair, whether transient or permanent, contribute to tumor development and progression. Yet, to replicate their DNA and proliferate, cancer cells need DNA repair mechanisms, perhaps even more so than normal cells. Moreover, efficient DNA repair mechanisms can enable cancer cells to resist radiotherapy and chemotherapy. We are entering a new era of cancer research in which patients will be stratified for appropriate therapy on the basis of their DNA repair status, rather than on the tissue of origin, and where combination treatments will include DNA repair inhibitors. The goal of our work is to use the acquired knowledge to exacerbate the sensitivity of cancer cells to radiotherapy and specific chemotherapeutic treatments.
- Bases moléculaires des rôles de CUX1 en tant que suppresseur de tumeur haploinsuffisant surexprimé dans la plupart des cancers humains Le gène CUX1 a été caractérisé comme un gène suppresseur de tumeur haploinsuffisant dans environ 20% des cancers. Cela signifie que l'inactivation d'un seul allèle de CUX1 est suffisante pour créer un phénotype favorable au développement tumoral. Pourtant, CUX1 est amplifié dans de nombreux cancers et est surexprimé dans plus de 70% des cancers humains. Nous étudions les activités transcriptionnelles et de réparation de l'ADN de CUX1 qui expliquent son double rôle dans le cancer. Molecular Bases for the Roles of CUX1 as a Haploinsufficient Tumor Suppressor that Is Overexpressed in Most Human Cancers The CUX1 gene has been characterized as a haploinsufficient tumor suppressor gene in approximately 20% of cancers. This means that the inactivation of only one CUX1 allele is sufficient to create a phenotype conducive to tumor development. Yet, CUX1 is amplified in many cancers and is overexpressed in more than 70% of human cancers. We investigate the transcriptional and DNA repair activities of CUX1 that explain its dual role in cancer.
- Facteurs auxiliaires stimulant les activités enzymatiques de Pol β La réparation par excision de base est la voie qui répare toutes les bases altérées, les sites apuriniques et les cassures simple brin. Chaque jour, une cellule normale subit environ 30 000 de telles lésions d'ADN. Ce nombre augmente dans les cellules cancéreuses car elles peuvent produire des niveaux excessifs de espèces réactives de l'oxygène ou exprimer des enzymes telles que des déaminases qui modifient les bases de l'ADN. Plusieurs facteurs de transcription ont été découverts pour stimuler les activités enzymatiques de l'une des nombreuses ADN glycosylases, qui élimine les bases altérées dans le génome pour initier la réparation par excision de base. Chacun de ces facteurs de transcription/facteurs de réparation d'ADN auxiliaires a également été trouvé pour stimuler les activités enzymatiques de Pol β, l'enzyme qui complète le processus de réparation par excision de base. Dans un projet, nous tentons d'identifier tous les facteurs auxiliaires de Pol β. Dans un projet distinct, nous étudions le mécanisme par lequel les facteurs auxiliaires peuvent stimuler Pol β. Auxiliary Factors that Stimulate the Enzymatic Activities of Pol β Base excision repair is the pathway that repairs all altered bases, abasic sites and single-strand breaks. Any normal cells suffers approximately 30,000 such DNA lesions every day. This number increases in cancer cells because they may produce excess levels of reactive oxygen species or express enzymes such as deaminases that modify DNA bases. A number of transcription factors were found the stimulate the enzymatic activities of one of the several DNA glycosylases, which removes altered bases in the genome to initiate base excision repair. Each of these transcription factors/auxiliary DNA repair factors were also found to stimulate the enzymatic activities of Pol β, the enzyme that completes the process of base excision repair. In one project, we attempt to identify all the auxiliary factors for Pol β. In a separate project, we investigate the mechanism by which auxiliary factors can stimulate Pol β.
- Le rôle de MYC, MYCN et MYCL en tant que facteurs auxiliaires dans la réparation par excision de base Les cellules lymphomateuses B qui continuent d'exprimer la déaminase induite par l'activation (AID) produisent un excès de résidus d'uracile dans leur génome. De manière similaire, les cellules cancéreuses qui expriment la déaminase APOBEC3A hébergent également de nombreux résidus d'uracile dans leur génome. Pour maintenir leur vitalité, ces cellules cancéreuses doivent rapidement éliminer les résidus d'uracile de leur génome et insérer la base correcte. Ces tâches sont accomplies par l'uracile DNA glycosylase (UDG) et Pol β, deux enzymes de la voie de réparation par excision de base. Nous avons découvert que les protéines MYC, largement caractérisées en tant que facteur de transcription, jouent un rôle important en tant que facteurs auxiliaires qui stimulent les activités enzymatiques de l'UDG et de Pol β, permettant ainsi aux cellules cancéreuses de survivre malgré la production excessive de résidus d'uracile. The Role of MYC, MYCN and MYCL as Auxiliary Factors in Base Excision Repair B cell lymphoma cells that continue to express the activation-induced deaminase (AID) produce an excess of uracil residues in their genome. Similarly, cancer cells that express the APOBEC3A deaminase also exhibit harbor many uracils in their genome. To maintain their fitness, these cancer cells must rapidly remove uracil residues from their genome and insert the correct base. These tasks are accomplished by the uracil DNA glycosylase (UDG) and Pol β, two enzymes of the base excision repair pathway. We found that the MYC proteins, which have been extensively characterized as transcription factor, play an important role as auxiliary factors that stimulate the enzymatic activities of UDG and Pol β and enable cancer cells to survive despite producing excess levels of uracils.
- Professor
Distinguished James McGill Professor
Rosalind and Morris Goodman Cancer Institute
Departments Oncology and Biochemistry
Faculty of Medicine and Health Sciences
McGill University
Our team
Major discoveries
- 2014 RAS-Transformation in Cancer Cells Requires CUX1-Dependent Repair of Oxidative DNA Damage.
- 2022 The DNA Repair Functions of BCL11A Suppresses Senescence and Promotes Continued Proliferation of Triple-Negative Breast Cancer Cells.
- 2022 Base Excision Repair Accessory Factors in Senescence Avoidance and Resistance to Treatments.
- 2023 The Function of BCL11B in Base Excision Repair Contributes to its Dual Roles as an Oncogene and a Haplo-Insufficient Tumor Suppressor Gene.
Research Partners
Get in touch
1001 Boul. Décarie
Montreal, Quebec H4A 3J1
Office: 414
Lab: 411
T. 514-398-5839
T. 514-398-5163
F. 514-398-6769
alain.nepveu@mcgill.ca
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