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Expression of mitochondrial genes and DNA-repair-related nuclear genes is altered in xeroderma pigmentosum fibroblasts

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  • Experimental Oncology
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Abstract

Differential hybridization was used to detect repair defects in xeroderma pigmentosum (XP) that are not amenable to current analyses. cDNA libraries were constructed from cytoplasmic RNA of normal and XP fibroblast strains (complementation groups A and D) and analyzed for differential gene expression. More than 40000 λgt10 cDNA clones were differentially screened with in vitro transcripts made from cDNA in the pBluescript vector. Six differential clones were detected in the libraries of the XP group A and D strains which caused stronger or weaker signals when probed with transcripts from XP strains than with those from the normal strains. Two clones coded for mitochondrial genes: mitochondrial 16 S rRNA and ATPase 6L. Overexpression of mitochondrial genes in XP may indicate that functions of the ATP-generating system are impaired since such functions are intensified whenever they become insufficient, for example as a consequence of DNA damage. It is tempting to assume that abnormal mitochondria are one of the causes for the neurological malfunctions in XP. Furthermore, densitometric analysis of Northern blots revealed that mRNA of lactate dehydrogenase, chain M, was less abundant in four XP group A strains (extent of reduction: 70%) and in two XP group D strains (extent of reduction: 58%). Enzyme activity was also diminished. In addition, mRNA of the gene for glyceraldehyde-3-phosphate dehydrogenase was less expressed in the same XP group A and D fibroblast strains investigated (reduction in both complementation groups: 50%). Both glycolytic enzymes have nuclear functions apart from their role in sugar metabolism. Lactate dehydrogenase, chain M, is identical to a helix-destabilizing protein; it is closely associated with chromatin and unfolded DNA, suggesting a role in DNA synthesis and transcription. The 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase is involved in transcription and was shown to be identical to uracil-DNA glycosylase, a base-excision repair enzyme. We presume that the nuclear functions of these glycolytic enzymes may be thwarted in the XP strains investigated and may account for malfunctions in XP, particularly for neurological disturbances.

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Author notes

  1. Heinz Walter Thielmann

    Present address: Division of Interaction of Carcinogens with Biological Macromolecules, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

  2. Xianmin Xia

    Present address: Cell Science Center, Inc., 10 Old Barn Road, 12946-1099, Lake Placid, New York, USA

Authors and Affiliations

  1. Division of Interaction of Carcinogens with Biological Macromolecules, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Xianmin Xia & Odilia Popanda

  2. Division of Cellular Biochemistry, German Cancer Research Center, Heidelberg, Germany

    Dieter Werner

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  1. Xianmin Xia
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  2. Dieter Werner
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  3. Odilia Popanda
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  4. Heinz Walter Thielmann
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This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 136 and WE 589/2-1

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Xia, X., Werner, D., Popanda, O. et al. Expression of mitochondrial genes and DNA-repair-related nuclear genes is altered in xeroderma pigmentosum fibroblasts. J Cancer Res Clin Oncol 120, 454–464 (1994). https://doi.org/10.1007/BF01191798

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