Chromosomes with high gene density are preferentially repaired in human cells.
It is known that DNA repair is heterogeneous in human cells since open chromatin, active genes and their transcribed strands are preferentially repaired. It is thus expected that DNA repair is clustered in chromosomes with high gene density. We have employed a DNA repair inhibitor, cytosine arabinoside (Ara-C), to convert ethyl methane sulfonate (EMS)-induced excision repairable lesions to chromosomal breaks, to check for the existence of heterogeneity of repair at the chromosome level. Chromosome staining by fluorescence in situ hybridization (FISH) was used to analyze breakage in chromosomes with diverse gene densities. These chromosomes were identified by means of the CpG island distribution after FISH with a CpG island-rich probe isolated from total human genomic DNA. Thus, three chromosomes with very high gene density (numbers 1, 19 and 20) were compared with two chromosomes with very low gene density (numbers 4 and 18) for clastogenicity and sensitivity to co-treatment with Ara-C and EMS. Our data indicate that those chromosome with higher gene density are more sensitive to a combination treatment with Ara-C and EMS, indicating that the level of excision repair synthesis is higher in those chromosome. It is therefore concluded that DNA excision repair is preferentially directed to chromosomes with high gene density. The implications of this finding in human biomonitoring using FISH techniques are discussed.
Surrallés
J
J
Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, The Netherlands. ibgb6@blues.uab.es
Sebastian
S
S
Natarajan
A T
AT
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002478:Cells, Cultured; D019457:Chromosome Breakage / Q000235:genetics; D002875:Chromosomes / Q000187:drug effects*; D002878:Chromosomes, Human, Pair 1 / Q000187:drug effects; D002887:Chromosomes, Human, Pair 18 / Q000187:drug effects; D002888:Chromosomes, Human, Pair 19 / Q000187:drug effects; D002890:Chromosomes, Human, Pair 20 / Q000187:drug effects; D002894:Chromosomes, Human, Pair 4 / Q000187:drug effects; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D005020:Ethyl Methanesulfonate / Q000494:pharmacology / Q000633:toxicity; D005796:Genes / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016296:Mutagenesis / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity
D000964:Antimetabolites, Antineoplastic; D009153:Mutagens; D003561:Cytarabine; D005020:Ethyl Methanesulfonate