Dynamics of the Genome - CNRS URA2171  


  HEADArcangioli Benoit / barcan@pasteur.fr
  MEMBERSBen hassine Samia / Dr Holmes Allyson / Roseaulin Laura / Pelloux Julie Schurra Catherine / Lavenir Armelle


  Annual Report

Genomic imprinting (Helen V. Crouse, 1960) is necessary for proper growth and development in many species, and as been implicated in cancer, aging and development in humans. The programmed strand-specific imprinting (SSB) at the mating-type locus, constitute a novel type of imprint, which continues to be actively studied in the laboratory. Because the homologous recombination process can be view as an integral part of DNA replication we wonder how the DNA is repaired in the G0/quiescent state. Recently, we began to work on a new form of single strand break repair pathway, which appears to be crucial in quiescent state.

Our previous works allowed us to show that a programmed strand-specific modified nick at the mat1 locus constitute a novel chromosomal imprinting. This DNA lesion is the initial event triggering mating-type switching in this yeast. Polar replication pausing and termination at mat1 is essential for the formation of the imprint.

Recently, we constructed and validated a powerful inducible nick and mating-type switching system. Starting with a homogenous cell population (a single mating-type and no break), we were able to study the kinetics of each cellular step. We found that the overall process of MT switching in S. pombe is a two-step process, involving two rounds of DNA replication (See Figure). This inducible genetic system allowed us to identify new genes require for imprinting.

The role of recombination in the recovery of stalled/collapsed replication forks is an essential process in maintaining genomic stability and defects in this pathway cause predisposition to many forms of diseases. We show that a unique collapsed replication fork at the mating-type locus required the homologous recombination enzymes for viability in fission yeast.

We have shown how the yeast Schizosaccharomyces pombe can mimic, at the single cell level, the syndrome observed in humans in the case of spinocerebellar ataxia known as SCAN1. This rare and severe neurodegenerative disease is characterized by a loss of balance and coordination in adolescents, and results in death around the age of 25. It is caused by the progressive death of cells that do not divide, particularly neurons from the cerebellum, responsible for transmitting information to limbs and the brain. Thanks to a strain mutated in homolog to the one affected in SCAN1 patients, we have been able to identify similarities in the “symptoms” observed: yeasts deficient in this geneprogram their own death when they do not divide, just like the post-mitotic neurons from SCAN1 patients.

Keywords: Stem cell, imprinting, replication, recombination, cancer, ataxia

Dynagen.jpg

Mating-type switching pattern (From Klar, 1990). P and M indicate the mating-type of the cell, the suffix u or s represents the unswitchable and switchable potential of the cell, respectively. For simplicity, only the P lineage is shown (mirror image of the M). The one-in four and the consecutive switching rules are indicated. The overall pattern is similar to stem cell division in higher eukaryotes.



  Publications

Holmes A., Kaykov, A. and Arcangioli B. (2005) Molecular and Cellular Dissection of mating-type switching steps in S. pombe. Mol. Cell. Biol., 25 : 303-311.

Xhemalce B, Miller KM, Driscoll R, Masumoto H, Jackson SP, Kouzarides T, Verreault A, Arcangioli B. (2007). Regulation of histone H3 lysine 56 acetylation in Schizosaccharomyces pombe. J Biol Chem., 282:15040-7.

Arcangioli B . Roseaulin L. and Holmes A. (2007) Mating-type switching in S. pombe. A. Aguilera and R. Rothstein (ed). Topic in Current Genetics TCG

Xhemalce B., Riising E.M., Baumann P., Dejean A., Arcangioli B. and Seeler J.S. (2007). Role of SUMO in the Dynamics of telomere maintenance in fission yeast. Proc Natl Acad Sci U S A. 104:893-8.

Laura Roseaulin, Yoshiki Yamada, Yasuhiro Tsutsui, Paul Russell, Hiroshi Iwasaki and Benoit Arcangioli. (2008)Mus81 is essential for sister chromatid recombination at broken replication forks. EMBO J. 27: 1378-1387





Activity Reports 2009 - Institut Pasteur
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