Role of Mismatch Repair in Age-related Diseases – University of Copenhagen

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Projects in Mismatch Repair in Age-related Diseases

The DNA repair system, mismatch repair (MMR), contributes to maintain genome integrity by primarily correcting errors that occur when the genome is replicated. This corrective function increases the fidelity of replication up to three orders of magnitude and prevents mutation accumulation.

Consequently, MMR malfunction brings about an age-dependent accumulation of mutations and predisposition to cancer development (Lynch syndrome). Surprisingly, MMR contradicts this corrective role and promotes DNA alterations at certain repetitive sequences. This non-canonical mutagenic activity is involved in the pathological expansion of trinucleotide repeats which is the underlying cause of neurodegenerative diseases such as Huntington’s disease, myotonic dystrophy and Friedreich’s ataxia and may influence the maintenance of telomeric repeats in cancer cells.

Our group is focused on understanding this dichotomy of behaviour exhibited by MMR and its relevance in age-related diseases. Our objective is to identify and characterize the factors that influence MMR activity and to decipher the conditions that drive the transition of a high fidelity DNA repair into a mutagenic one.

In order to address the role of MMR in disease, we are using a wide range of approaches including proteomics studies, high content microscopy and biochemistry analyses.

Our final goal is to contribute to a better understanding of the molecular mechanism of disease, and to aid the design of therapies for prevention or cure of ailments associated with our aging process.