• E-mail :[email]
  • Phone : +33 4 34 35 99 73
  • Location : Montpellier, France
Last update 2011-04-05 13:46:43.997

Domenico MAIORANO PhD Genetics and Cell Biology

Course and current status

1995. PhD at the University of Oxford (England, UK). Cell cycle regulation of DNA replication in fission yeast.

1996. Research Assistant at the University of Oxford.

1997-2001. Postdoctoral fellow at the Institute Jacques Monod (Paris, France), then at the Institute of Human Genetics of Montpellier (France). Biochemistry of DNA replication in Xenopus in vitro systems.

2001. Staff researcher employed by INSERM at the CNRS Institute of Human Genetics of Montpellier (France)

Since April 2007. Group leader of the "Genome Surveillance and Stability" team at the Institute of Human Genetics of Montpellier (France). Biochemistry and Cell Biology of DNA damage and replication checkpoints.

 

Membership

Member of Trinity College, Oxford (England, UK)

Member of Faculty of 1000 Biology “Nuclear Structure and Function Section”

Member of the American Association for the Advancement of Science (AAAS)

Member of the French Society of Cell Biology

Biography published by Marquis “Who’s Who in the World”, “Who’s Who in Healthcare and Medicine”,  “ Who’s Who in Science and Engineering”.

Scientific summary

Our team is interested in the regulation of DNA damage and replication checkpoints. These surveillance mechanisms are crucial in the maintenance of genomic stability when the integrity of the DNA is compromised. Checkpoint signals are generated in the presence of DNA lesions (such as DNA strands breaks, telomer integrity, replication forks arrest) so to block cell division and activate repair pathways necessary to regenerate the normal state of the DNA. The arrest of DNA replication forks during the S phase of the cell cycle, the exposure to chemical compounds, and endogenous cues, such as free oxygen radicals or the metabolism of the DNA itself, constitute major sources of mutations that continuously threaten the integrity of the genome of the cells of the human body. A strong genomic instability is a hallmark of cancer cells (telomeric fusions, translocations, duplications and deletions) and is responsible for the activation of aberrant genetic programmes. Many genes of the checkpoint pathway have been found mutated in a variety of cancer-susceptibility syndromes, in particular at an aggressive stage.

Although the genes controlling the DNA damage and replication checkpoints are well conserved throughout evolution, a number of genes are only found in vertebrates, and are also found often mutated in several cancers. It is likely that more genes implicated in the regulation of the DNA damage checkpoint, that are not conserved in simple eukaryotes, may exist. We are using a functional screen and a proteomic approach to search for new, vertebrate-specific, checkpoint genes and proteins.

    We are interested in understanding the molecular mechanism of sensors activation, the proteins that recognize the lesions. In particular, the structures recognized by the sensor and the consequences of this recognition upon the function of the sensor protein (post-translational modifications, structural changes, interaction with specific partners) are not currently known. The RPA complex is a putative sensor of the DNA damage and replication checkpoints. It is currently thought that the the single stranded DNA generated at DNA replication forks arrested by DNA damage or by drugs that inhibit the replicatives DNA polymerases, is the primary signal that triggers activation of the checkpoint. The single stranded DNA is a substrate of the  RPA complex, that in turn recruits certains sensor proteins, such as ATR, and initiates the checkpoint  signal. We are currently testing this model.

We are also studying the interaction between the DNA replication fork and the system that detects and repair DNA single strand breaks. We have recently shown that the DNA repair protein, XRCC1, is important to bloc the progression of the replication fork across single strand breaks by interaction with DNA primase, the protein that begins DNA synthesis (Lévy et al., 2009). This regulation may be important to avoid conversion of single strand breaks into double strand breaks by the passage of the  replication fork, thus preserving genome stability.

 

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