Oxygen, although essential for life, is dangerous to cells because it
forms reactive oxygen species (ROS) that cause damage to nucleic acids
and proteins and one major ageing theory holds, that accumulation of
oxidative damage constitutes a major causes of aging and age-related
diseases. Furthermore, replication and DNA damage repair are central
to genomic stability. Mutations in genes coding for proteins involved
in replication and/or DNA damage repair pathways lead to premature ageing
(progeroid syndromes), neurodegeneration and frequently cancer. Hence,
such mutations cause phenotypes recapitulating features of
"normal" ageing, e.g. gray hair, cataracts and increased
incidence of cancer. Moreover, certain steps along the pathways repairing
oxidative DNA damage require "rescue" proteins, which remove
abortive ligation intermediates caused by so-called "dirty strand
breaks" and mutations in these proteins may lead to neurodegeration
in humans.
Protein damage by ROS frequently leads to non-reversible
modification of the polypeptide chain, including chain breaks, which in
turn compromises or abolishes protein function. The oxidation of
methionine to methionine sulfoxide, however, can be "repaired"
by methionine sulfoxide reductases (MSRs).
Our goal is to solve the molecular structures of proteins involved in
genome maintenance and damage repair and to characterise their molecular
interactions with substrates, in order to provide insight
into their respective mechanism of action and, thereby, to assess their
role during "normal" ageing.
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Collaborations:
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Z.Q. Wang, H. Pospiech, F. Grosse (FLI)
S. Heinemann
(FSU Jena)
W. Meyer-Klaucke
(DESY Hamburg)
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