Scientific topics
Keywords
Jean-Sébastien Hoffmann PhD Cancer Genetics
Course and current status
Since 2011 : Group Leader of the INSERM Team "Regulation of DNA Replication and genetic Instability in Cancers” at Cancer Research Center of Toulouse INSERM UMR1037, University of Toulouse
1 Professor, 2 Researchers CNRS + INSERM, 1 CNRS Technician, 1 Post-doctoral Fellow, 2 PhD students, & 2 undergraduate students
Scientific Fields : Cancer, Molecular Genetics, DNA Replication and replication Checkpoint, DNA Repair and Recombination, Mutagenesis, Chromosmome Instability, Fragile site
1998-2010: Group Leader of the CNRS Team "Genetic Instability and cancer"
1 Professor, 3 Researchers CNRS + INSERM, 1 CNRS Technician, 1 Post-doctoral Fellow, 3 PhD students, & 2 undergraduate students
Scientific Fields : Cancer, Molecular Genetics, DNA Replication and replication Checkpoint, DNA Repair and Recombination, Mutagenesis, Chromosmome Instability,
Dec.93/Sept.98 : Institut de Pharmacologie et de Biologie Structurale
Research Scientist in the Genotoxicology group
Field : Mutagenic replication and cisplatin resistance
June 91/Nov 93 : “Senior Fellow” at the "Joseph Gottstein Memorial Cancer Research Laboratory" (Director : Dr. Lawrence Loeb; Department ofPathology , School of Medicine ; University of Washington ; Seattle (USA);
Fields : Mutagenesis and DNA Replication, HIV Reverse Transcriptase
Dec 88/June 91 : PhD student (CNRS UPR 9062, Laboratoire de Pharmacologie et de Toxicologie Fondamentales) Genotoxicology and therapeutic Resistance
Avril - June 1989 : Laboratory of Biochemical veterinary - Prof U. Hübscher (University of Zürich – Swizerland) Field : Biochemistry of eukaryotic DNA polymerases
Scientific summary
Genetic instability plays a major role in cancer. Recent results suggest that this instability is mostly generated in S phase, during the duplication of the genome. However, the molecular mechanisms involved in this replication stress in cancer cells have remained elusive. DNA replication represents a critical process because endogenous and exogenous events challenge genome stability by interfering with the progression of replication forks. Failure to protect stalled forks or to process them appropriately for replication restart results in the accumulation of genomic aberrations (“replication stress”). Our research projects (2005-2009) explored the importance in these processes of a recently-discovered DNA polymerases family, called specialized or translesion synthesis (TLS) DNA polymerases whose role thus far was known to take over from stalled replicative polymerases and allow synthesis through a variety of DNA lesions. We performed (i) basic science to identify unexplored new functions of TLS DNA polymerases during the normal process of DNA replication in absence of external damage as well as (ii) translationnal approaches aiming to understand how cancer cells use altered expression pattern of TLS genes to promote genomic instability and validate specific expression patterns of these genes as diagnostic, prognostic and/or predictive markers.
We are now investigating the molecular mechanisms involved in the replication stress that trigger genetic instability in cancer cells by focusing on two mechanisms dealing with arrested forks (i) translesion synthesis (TLS) by the TLS DNA polymerases, specialized enzymes that can synthesize DNA through lesions that cannot be replicated by the replicative DNA polymerases and (ii) the DNA replication checkpoint (DRC), an essential pathway for the maintenance of genomic integrity. By using human cell lines and transgenic mice model systems, we are addressing the role of the functional interplay between both pathways for the replication of chromosomal fragile sites, which have been implicated in chromosome rearrangements and whose expression is one of the earliest markers of tumorigenesis. This research program will provide new clues to understand how genetic instability arises in normal cells and how cancer cells handle with this instability to replicate their genome, opening the development of original diagnostic and prognostic strategies.
