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Developmental and Genetic Analysis of DNA Double-Strand Break Repair

Objective

The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.

Field of science

  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

ACADEMISCH ZIEKENHUIS LEIDEN
Address
Albinusdreef 2
2333 ZA Leiden
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 022 269,55
Principal investigator
Marcel Tijsterman (Dr.)
Administrative Contact
Liesbeth Dorama (Ms.)

Beneficiaries (2)

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands
EU contribution
€ 1 022 269,55
Address
Albinusdreef 2
2333 ZA Leiden
Activity type
Higher or Secondary Education Establishments
Principal investigator
Marcel Tijsterman (Dr.)
Administrative Contact
Liesbeth Dorama (Ms.)
KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW

Participation ended

Netherlands
EU contribution
€ 37 730,45
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Activity type
Other
Administrative Contact
Don Van Velzen (Mr.)