Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines.
Common fragile sites (CFSs) are specific chromosome regions that exhibit an increased frequency of breaks when cells are exposed to a DNA-replication inhibitor such as aphidicolin. PARK2 and DMD, the causative genes for autosomal-recessive juvenile Parkinsonism and Duchenne and Becker muscular dystrophy, respectively, are two very large genes that are located within aphidicolin-induced CFSs. Gross rearrangements within these two genes are frequently observed as the causative mutations for these diseases, and similar alterations within the large fragile sites that surround these genes are frequently observed in cancer cells. To elucidate the molecular mechanisms underlying this fragility, we performed a custom-designed high-density comparative genomic hybridization analysis to determine the junction sequences of approximately 500 breakpoints in germ cell lines and cancer cell lines involving PARK2 or DMD. The sequence signatures where these breakpoints occur share some similar features both in germ cell lines and in cancer cell lines. Detailed analyses of these structures revealed that microhomologies are predominantly involved in rearrangement processes. Furthermore, breakpoint-clustering regions coincide with the latest-replicating region and with large nuclear-lamina-associated domains and are flanked by the highest-flexibility peaks and R/G band boundaries, suggesting that factors affecting replication timing collectively contribute to the vulnerability for rearrangement in both germ cell and somatic cell lines.
Mitsui
Jun
J
Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Takahashi
Yuji
Y
Goto
Jun
J
Tomiyama
Hiroyuki
H
Ishikawa
Shunpei
S
Yoshino
Hiroyo
H
Minami
Narihiro
N
Smith
David I
DI
Lesage
Suzanne
S
Aburatani
Hiroyuki
H
Nishino
Ichizo
I
Brice
Alexis
A
Hattori
Nobutaka
N
Tsuji
Shoji
S
D001483:Base Sequence; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D043283:Chromosome Fragile Sites; D004261:DNA Replication; D016189:Dystrophin / Q000235:genetics*; D015321:Gene Rearrangement; D056426:Genetic Loci; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020734:Parkinsonian Disorders / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
C484258:DMD protein, human; D016189:Dystrophin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein