Chromosome Stability Group – University of Copenhagen

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Projects in Chromosome Stability Group

Our laboratory analyzes the mechanisms by which human cells maintain the integrity of their chromosomes, and how chromosomal instability contributes to human ageing. We utilize two general approaches:

(1) Characterization of DNA repair and maintenance processes that influence the incidence or severity of age-related pathologies, including neurodegeneration.

(2) Molecular analysis of naturally-occurring (but rare) syndromes in the human population that manifest as premature ageing.

To identify new factors that prevent neurodegeneration, we are conducting unbiased genetic screens for factors that influence the rate/efficiency of DNA strand break repair. This strategy was undertaken because several genes involved in the repair of single strand breaks in DNA are mutated in disorders associated with neurodegenerative phenotypes such as ataxia and seizures. Using this approach, we have identified a number of new candidate genes that regulate the process of DNA strand break repair and the functions of these proteins are currently being investigated further.

We also have a longstanding interest in the RecQ family of DNA helicases, largely because mutations in three of the family members, BLM, WRN and RECQL4, cause human syndromes associated with premature ageing phenotypes and specific developmental defects. We combine protein biochemistry on purified RecQ enzymes with molecular/cell biological analysis of cells lacking each of the RecQ helicases. For example, we have studied extensively the role for BLM in protecting cells from genome instability in both S-phase and mitosis. This led to the identification of ultra-fine anaphase DNA bridges (UFBs) which are thread-like DNA structures connecting the separating sister chromatids in the anaphase of mitosis. These UFBs arise from inherently unstable regions of our genomes, and are detectable in every human cell division. Analysis of UFBs subsequently led us into studies of a protein that associates with BLM on the UFBs – called PICH. PICH possesses the unique property of being able to detect stretched DNA under tension, which is consistent with its proposed role as a sensor/regulator of anaphase DNA bridges. Our ongoing analyses are aimed at determining how RecQ helicases, PICH, and their associated factors cooperate to promote chromosomal stability throughout our lifespan. We are also examining how and why inherently ‘fragile’ or unstable regions of the human genome (e.g. centromeres, telomeres, and common or rare fragile sites) directly contribute to genome instability during aging.