c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus.
In previous work, we showed that telomeres of normal cells are organized within the 3D space of the interphase nucleus in a nonoverlapping and cell cycle-dependent manner. This order is distorted in tumor cell nuclei where telomeres are found in close association forming aggregates of various numbers and sizes. Here we show that c-Myc overexpression induces telomeric aggregations in the interphase nucleus. Directly proportional to the duration of c-Myc deregulation, we observe three or five cycles of telomeric aggregate formation in interphase nuclei. These cycles reflect the onset and propagation of breakage-bridge-fusion cycles that are initiated by end-to-end telomeric fusions of chromosomes. Subsequent to initial chromosomal breakages, new fusions follow and the breakage-bridge-fusion cycles continue. During this time, nonreciprocal translocations are generated. c-Myc-dependent remodeling of the organization of telomeres thus precedes the onset of genomic instability and subsequently leads to chromosomal rearrangements. Our findings reveal that c-Myc possesses the ability to structurally modify chromosomes through telomeric fusions, thereby reorganizing the genetic information.
Louis
Sherif F
SF
Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Avenue, Winnipeg, MB, Canada R3E 0V9.
Vermolen
Bart J
BJ
Garini
Yuval
Y
Young
Ian T
IT
Guffei
Amanda
A
Lichtensztejn
Zelda
Z
Kuttler
Fabien
F
Chuang
Tony C Y
TC
Moshir
Sharareh
S
Mougey
Virginie
V
Chuang
Alice Y C
AY
Kerr
Paul Donald
PD
Fest
Thierry
T
Boukamp
Petra
P
Mai
Sabine
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D020223:Chromosome Painting; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase / Q000235:genetics / Q000502:physiology*; D007621:Karyotyping; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc