Dataset Information

Location of DNA damage by charge exchanging repair enzymes: effects of cooperativity on location time.

ABSTRACT:

Background

How DNA repair enzymes find the relatively rare sites of damage is not known in great detail. Recent experiments and molecular data suggest that individual repair enzymes do not work independently of each other, but interact with each other through charges exchanged along the DNA. A damaged site in the DNA hinders this exchange. The hypothesis is that the charge exchange quickly liberates the repair enzymes from error-free stretches of DNA. In this way, the sites of damage are located more quickly; but how much more quickly is not known, nor is it known whether the charge exchange mechanism has other observable consequences.

Results

Here the size of the speed-up gained from this charge exchange mechanism is calculated and the characteristic length and time scales are identified. In particular, for Escherichia coli, I estimate the speed-up is 50000/N, where N is the number of repair enzymes participating in the charge exchange mechanism. Even though N is not exactly known, a speed-up of order 10 is not entirely unreasonable. Furthermore, upon over expression of all the repair enzymes, the location time only varies as N-1/2 and not as 1/N.

Conclusion

The revolutionary hypothesis that DNA repair enzymes use charge exchange along DNA to locate damaged sites more efficiently is actually sound from a purely theoretical point of view. Furthermore, the predicted collective behavior of the location time is important in assessing the impact of stress-ful and radioactive environments on individual cell mutation rates.

SUBMITTER: Eriksen KA

PROVIDER: S-EPMC1142343 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Publications

Location of DNA damage by charge exchanging repair enzymes: effects of cooperativity on location time.

Eriksen Kasper Astrup KA

Theoretical biology & medical modelling 20050408

<h4>Background</h4>How DNA repair enzymes find the relatively rare sites of damage is not known in great detail. Recent experiments and molecular data suggest that individual repair enzymes do not work independently of each other, but interact with each other through charges exchanged along the DNA. A damaged site in the DNA hinders this exchange. The hypothesis is that the charge exchange quickly liberates the repair enzymes from error-free stretches of DNA. In this way, the sites of damage are ...[more]

PMID: 15819980

Similar Datasets

Project description:Base excision repair is hindered by nucleosomes.Outwardly oriented uracils near the nucleosome center are efficiently cleaved; however, polymerase ? is strongly inhibited at these sites.The histone octamer presents different levels of constraints on BER, dependent on the structural requirements for enzyme activity.Chromatin remodeling is necessary to prevent accumulation of aborted intermediates in nucleosomes. Packaging of DNA into chromatin affects accessibility of DNA regulatory factors involved in transcription, replication, and repair. Evidence suggests that even in the nucleosome core particle (NCP), accessibility to damaged DNA is hindered by the presence of the histone octamer. Base excision repair is the major pathway in mammalian cells responsible for correcting a large number of chemically modified bases. We have measured the repair of site-specific uracil and single nucleotide gaps along the surface of the NCP. Our results indicate that removal of DNA lesions is greatly dependent on their rotational and translational positioning in NCPs. Significantly, the rate of uracil removal with outwardly oriented DNA backbones is 2-10-fold higher than those with inwardly oriented backbones. In general, uracils with inwardly oriented backbones farther away from the dyad center of the NCP are more accessible than those near the dyad. The translational positioning of outwardly oriented gaps is the key factor driving gap filling activity. An outwardly oriented gap near the DNA ends exhibits a 3-fold increase in gap filling activity as compared with one near the dyad with the same rotational orientation. Near the dyad, uracil DNA glycosylase/APE1 removes an outwardly oriented uracil efficiently; however, polymerase ? activity is significantly inhibited at this site. These data suggest that the hindrance presented by the location of a DNA lesion is dependent on the structural requirements for enzyme catalysis. Therefore, remodeling at DNA damage sites in NCPs is critical for preventing accumulation of aborted intermediates and ensuring completion of base excision repair.

Dataset Information

Location of DNA damage by charge exchanging repair enzymes: effects of cooperativity on location time.

Background

Results

Conclusion

Publications

Location of DNA damage by charge exchanging repair enzymes: effects of cooperativity on location time.

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