Mitomycin C-induced pairing of heterochromatin reflects initiation of DNA repair and chromatid exchange formation.
Chromatid interchanges induced by the DNA cross-linking agent mitomycin C (MMC) are over-represented in human chromosomes containing large heterochromatic regions. We found that nearly all exchange breakpoints of chromosome 9 are located within the paracentromeric heterochromatin and over 70% of exchanges involving chromosome 9 are between its homologues. We provide evidence that the required pairing of chromosome 9 heterochromatic regions occurs in G(0)/G(1) and S-phase cells as a result of an active cellular process initiated upon MMC treatment. By contrast, no pairing was observed for a euchromatic paracentromeric region of the equal-sized chromosome 8. The MMC-induced pairing of chromosome 9 heterochromatin is observed in a subset of cells; its percentage closely mimics the frequency of homologous interchanges found at metaphase. Moreover, the absence of pairing in cells derived from XPF patients correlates with an altered spectrum of MMC-induced exchanges. Together, the data suggest that the heterochromatin-specific pairing following MMC treatment reflects the initiation of DNA cross-link repair and the formation of exchanges.
Abdel-Halim
H I
HI
Department of Toxicogenetics, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands.
Natarajan
A T
AT
Mullenders
L H F
LH
Boei
J J W A
JJ
D002478:Cells, Cultured; D023902:Chromosome Pairing / Q000187:drug effects / Q000502:physiology*; D002898:Chromosomes, Human, Pair 8 / Q000187:drug effects / Q000502:physiology; D002899:Chromosomes, Human, Pair 9 / Q000187:drug effects / Q000502:physiology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006570:Heterochromatin / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007399:Interphase / Q000502:physiology; D008677:Metaphase / Q000502:physiology; D016685:Mitomycin / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000502:physiology*; D014983:Xeroderma Pigmentosum / Q000235:genetics
D003432:Cross-Linking Reagents; D006570:Heterochromatin; D016685:Mitomycin