Malignant and nonmalignant brain tissues differ in their messenger RNA expression patterns for ERCC1 and ERCC2.
Perturbation of the DNA repair process appears to be responsible for the occurrence of a number of human diseases, which are usually associated with a propensity to develop internal malignancies and/or disorders of the central nervous system. We have been interested in the possibility that a subtle abnormality in DNA repair competency might be associated with the transformation of nonmalignant cells to the malignant state. To study this question, we assayed malignant and nonmalignant brain tissues from 19 individuals for mRNA expression levels of the human DNA repair genes ERCC1, ERCC2, and XPAC and for differential splicing of the ERCC1 transcript. We separately compared expression levels of these genes in the following situations: concordance of expression within malignant tissues; concordance of expression within nonmalignant tissues; concordance between malignant and nonmalignant tissues within individuals of the cohort; and concordance of gene expression between two nonmalignant tissue sites within a single individual. Linear regression analyses of mRNA values obtained suggested orderly concordance of these three DNA repair genes in nonmalignant tissues within the patient cohort and an excellent concordance of these genes between two separate biopsy sites from the same individual. In contrast, malignant tissues showed disruption of concordance between the full-length ERCC1 transcript and ERCC2, which have excision and helicase functions, respectively. Furthermore, within the same individuals, malignant tissues were discordant with nonmalignant tissues for ERCC1 and ERCC2, although concordance for XPAC was preserved. These data suggest that one molecular characteristic of human malignancy may be the disruption of the normal relationship between the excision and the helicase functions of the nucleotide excision repair pathway.
Dabholkar
M D
MD
Medical Ovarian Cancer Section, National Cancer Institute, Bethesda, Maryland 20892.
Berger
M S
MS
Vionnet
J A
JA
Egwuagu
C
C
Silber
J R
JR
Yu
J J
JJ
Reed
E
E
D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases; D006801:Humans; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D014157:Transcription Factors; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human