Dynamics of the Genome - CNRS URA2171  


  HEADArcangioli Benoit / barcan@pasteur.fr
  MEMBERSSchurra Catherine / Philippe Quillardet / Genevieve Janvier / Claire Denis / Catherine Adjutor


  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, constitutesa 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 have shown that S. pombe is a good cellular model for degenerative diseases.

Our previous works allowed us to show that a programmed strand-specific modified nick at the mat1 locus constitute 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 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. This inducible genetic system allowed us to identify new genes require for imprinting, including the Lysine Specific Demethylase 1, Lsd1. Lsd1 is one of the master players in imprinting in higher eukaryotes and has a key function for MT switching in S. pombe. Furthermore its role on MT switching seems to be beyond its transcriptional function, revealing an unexpected function for replication fork progression and asymmetric cell division. We were also very happy to collaborate with R. Martienssen’s lab (CSHL, USA) in an effort revealing a new interplay between retrotransposons integration and replication fork progression.

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 the gene homolog to the one affected in SCAN1 patients, we have been able to identify similarities in the “symptoms” observed: yeasts deficient in this gene,program their own death when they do not divide, just like the post-mitotic neurons from SCAN1 patients.

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



  Publications

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.

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

Ben Hassine S, Arcangioli B.(2009) Tdp1 protects against oxidative DNA damage in non-dividing fission yeast. EMBO J. 28: 632-40.

Arcangioli B, Ben Hassine S. (2009) Unrepaired oxidative DNA damage induces an ATR/ATM apoptotic-like response in quiescent fission yeast. Cell Cycle. 15: 2326-31.

Mikel Zaratiegui, Matthew W. Vaughn, Danielle V. Irvine, Derek Goto, Stephen Watt, Jürg Bähler, Benoit Arcangioli, Robert A. Martienssen.Centromere-binding protein B preserves genome integrity at replication forks paused by Retrotransposon LTR, Nature in press





Activity Reports 2010 - Institut Pasteur
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