c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus

Abstract

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.genomic instability ͉ 3D nucleus ͉ breakage-bridge-fusion

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…Once aggregates form and fusions occur, BBF cycles result and with such BBF cycles, the genetic information of the chromosomes will be remodeled [Louis et al, 2005]. TAs and fusions are different from the reversible telomeric associations that have been reported for Chinese hamster embryonic cells [Slijepcevic et al, 2000].…”

“…Metaphase chromosomes reflect events that occurred prior to the metaphase being examined and, with respect to some aberrations, researchers infer from studying the metaphase chromosomes that 'telomere dysfunctions' were likely. For example, unbalanced translocations, dicentric chromosomes, and terminally deleted chromosomes suggest a defect in telomeres that may involve capping defects, DNA damage affecting the telomeric ends, oncogene activation or other stimuli [Artandi et al, 2000;Gisselsson et al, 2001;Lo et al, 2002;Deng et al, 2003;Murnane and Sabatier, 2004;Louis et al, 2005].…”

“…Various numbers and sizes of such telomeric aggregates (TAs) can be found in tumor nuclei [Chuang et al, 2004]. The formation of TAs is independent of telomere length and telomerase activity [Louis et al, 2005].…”

“…One type of telomere dysfunction involves critically short telomeres [DePinho and Polyak, 2004]. The other one involves the formation of TAs and is independent of telomere size or telomerase activity [Chuang et al, 2004;Louis et al, 2005]. Both types of telomeric dysfunction can lead to BBF cycles that contribute to deletions, gene amplification, non-reciprocal translocation, and overall genetic changes that are associated with tumorigenesis [Artandi et al, 2000;DePinho and Polyak, 2004;Murnane and Sabatier, 2004].…”

“…Importantly, a BBF cycle is not a single event. One BBF cycle initiates the next and so forth until no more free ends persist to permit fusions with other chromosomes [McClintock, 1941[McClintock, , 1942Louis et al, 2005].…”