Repair in Eukaryotes

Many of the repair systems described for bacteria have counterparts in animals. However, these are usually less well characterized and much of our knowledge comes from finding eukaryotic proteins that are homologous to bacterial DNA repair enzymes. Defects in human DNA repair systems cause assorted health problems. In particular, the higher mutation rates that occur in the absence of DNA repair cause a higher frequency of various forms of cancer.

polymerase eta (h) A repair DNA polymerase in animals that can replicate past thymine dimers

UmuD

UmuD

UmuC

Genes expressed when LexA is degraded

Promotes cleavage

Promotes cleavage

D'2C

complex delays DNA replication

D'2C

Polymerase V (error - prone)

Polymerase V (error - prone)

For example, the human hMSH2 (human MutS homologue 2) gene encodes a protein very similar to the MutS protein of E. coli. Defects in this gene greatly increase the likelihood of several types of cancer. Such patients have a relatively high frequency of short deletions and insertions that would normally be corrected by the mismatch repair system (due to MutSLH in E. coli). Curiously, when the normal human hMSH2 gene is cloned and expressed in E. coli it increases the bacterial mutation frequency! This is apparently due to interference between hMSH2 and MutS. Patients with a defective BRCA1 (breast cancer A1) gene are more susceptible to breast and ovarian cancer. The BRCA1 protein is involved in both the mending of double-strand breaks and transcription-coupled excision repair. These processes are defective when the BRCA1 gene is damaged. The role of mutation and DNA repair in cancer is extremely complex and many details are still obscure.

The recessive hereditary disorder xeroderma pigmentosum is due to a failure of the excision repair system that removes thymine dimers and other bulky base adducts. Defects in any of approximately ten genes involved in excision repair will give xeroderma pigmentosum. The result is hypersensitivity of the skin to sunlight and ultraviolet radiation.

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