Some Repair Enzymes Are Multifunctional

Somewhat surprising is the recent observation that DNA repair proteins can serve other purposes. For example, some repair enzymes are also found as components of the large TFIIH complex that plays a central role in gene transcription (Chapter 37). Another component of TFIIH is involved in cell cycle regulation. Thus, three critical cellular processes may be linked through use of common proteins. There is also good evidence that some repair enzymes are involved in gene rearrangements that occur normally.

In patients with ataxia-telangiectasia, an autosomal recessive disease in humans resulting in the development of cerebellar ataxia and lymphoreticular neoplasms, there appears to exist an increased sensitivity to damage by x-ray. Patients with Fanconi's anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of cross-linking damage.

Ku and DNA-PK bind |

Approximation

Unwinding

Alignment and base pairing

Ligation

Figure 36-25. Double-strand break repair of DNA. The proteins Ku and DNA-dependent protein kinase combine to approximate the two strands and unwind them. The aligned fragments form base pairs; the extra ends are removed, probably by a DNA-PK-associated endo- or exonuclease, and the gaps are filled in; and continuity is restored by ligation.

All three of these clinical syndromes are associated with an increased frequency of cancer. It is likely that other human diseases resulting from disordered DNA repair capabilities will be found in the future.

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