Anita Krisko

1 Mediterranean Institute for Life Sciences, Split, Croatia, 2 INSERM U1001, Faculté de Médecine, 

Université R. Descartes Paris-5, Paris, France

, Miroslav Radman

1,2

*

Abstract

Although the genome contains all the information necessary for maintenance and perpetuation of life, it is the proteome

that repairs, duplicates and expresses the genome and actually performs most cellular functions. Here we reveal strong

phenotypes of physiological oxidative proteome damage at the functional and genomic levels. Genome-wide mutations

rates and biosynthetic capacity were monitored in real time, in single Escherichia coli cells with identical levels of reactive

oxygen species and oxidative DNA damage, but with different levels of irreversible oxidative proteome damage

(carbonylation). Increased protein carbonylation correlates with a mutator phenotype, whereas reducing it below wild type

level produces an anti-mutator phenotype identifying proteome damage as the leading cause of spontaneous mutations.

Proteome oxidation elevates also UV-light induced mutagenesis and impairs cellular biosynthesis. In conclusion, protein

damage reduces the efficacy and precision of vital cellular processes resulting in high mutation rates and functional

degeneracy akin to cellular aging.

Author Summary

Cellular life is maintained by the activities of proteins that,

together, prevent molecular damage from occurring in the

first place and repair damaged DNA, proteins and other

damaged cellular components. Cellular fitness decreases

due to the fact that these proteins are themselves subject

to damage, leading to the progressive degeneracy of

cellular functions due to diminishing protein activity and

decreased precision. The ultimate liability to protein

function is the irreversible oxidative protein modification,

protein carbonylation. In our study, we have altered the

intrinsic susceptibility of proteins to oxidative damage via

alterations of translation fidelity and the accuracy of

protein folding. We have found that the increased quality

of proteome leads to an improved biosynthetic capacity of

cells, as well as to decreased mutation rates. Since cellular

aging can be defined as a progressive loss of nearly all vital

cellular functions and an increase in mutation rates, this

work suggests that oxidative proteome damage may be

the most likely cause of aging and age-related diseases.

Citation: Krisko A, Radman M (2013) Phenotypic and Genetic Consequences of Protein Damage.

 PLoS Genet 9(9): e1003810. doi:10.1371/journal.pgen.1003810

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