Pathology of DNA Replication
Themes and areas of research : Quantitative biology and modeling , Development and evolution , Cellular dynamics and signaling , Genome and chromosome dynamics , Models , Molecular and cellular pathologies
Genetic instability is a major feature of tumor cells and is associated with the process of carcinogenesis in humans. In many cases, such instability occurs during the S phase and is due to DNA replication defects. The enzymatic machinery of replication used to copy and reproduce the DNA is called "replisome". Replisome progression is subject to numerous control systems because its disruption can produce changes in the genome. DNA replication may be hampered by barriers that slow, temporarily stop or block the progression of replicative DNA polymerases. These obstacles may have different causes: a) secondary structures in DNA, b) complex DNA-protein, c) changes in chromatin and d) DNA damage. If the arrested replication forks are not appropriately processed , chromosomal rearrangements (translocations, inversions or deletions) may occur and contribute to early stages of carcinogenesis. In this context, we study the functions of translesional DNA polymerases that may contribute to bypass break sites. Actually, we think that it is important to understand these aspects of DNA replication, both in terms of mechanisms of emergence of such obstacles and their functional consequences.
We study the molecular mechanisms of replication fork barriers induced by replicative stress, using human cell lines models. To do this, we use technologies such as two-dimensional gels to analyze intermediate forms of DNA replication, "ChIP-on-chip" methods and high-throughput sequencing. This allows us to locize the sites of replication fork pauses in the entire genome. In the long run, our work will help us better understand how defects caused by abnormal arrest of replication forks can contribute to the development of diseases associated with genomic instability, especially cancers. Moreover, thanks to high throughput approaches we explore the cancer genomic databases to identify molecular alterations that affect DNA metabolism and its control during the cell cycle.
Sélection of Publications
Fauchereau F, Shalev S, Chervinsky E, Fruchter RB, Legois B, Fellous M, Caburet S, Veitia RA.
A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency.
Clin Genet. 2016 Jan 14.
Baldacci G, Hoffmann JS, Cadoret JC.
Impact of the DNA polymerase Theta on the DNA replication program.
Genom Data. 2014 Dec 5;3:90-3.
Maric C, Bénard M.
Replication forks reverse at high frequency upon replication stress in Physarum polycephalum.
Chromosoma. 2014 Dec;123(6):577-85.
Fernandez-Vidal A, Guitton-Sert L, Cadoret JC, Drac M, Schwob E, Baldacci G, Cazaux C, Hoffmann JS.
A role for DNA polymerase θ in the timing of DNA replication.
Nat Commun. 2014 Jul 3;5:4285.
Delagoutte E, Heneman-Masurel A, Baldacci G.
Single-stranded DNA binding proteins unwind the newly synthesized double-stranded DNA of model miniforks.
Biochemistry 2011 50:932-944
Delagoutte E,Baldacci G.
5'CAG and 5'CTG Repeats Create Differential Impediment to the Progression of a Minimal Reconstituted T4 Replisome Depending on the Concentration of dNTPs.
Mol Biol Int. 2011;2011:213824.