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

Mai, Sabine; Garini, Yuval

doi:10.1002/jcb.20760

Cited by 83 publications

(94 citation statements)

References 50 publications

(75 reference statements)

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“…Heterochromatin Protein 1 (HP1) has been shown to form a complex with A-type lamins and LAP-2α, 49 and therefore could participate in the and their relevance for telomere metabolism remain unknown. 42 Interestingly, the 3D organization of telomeres is altered in tumor cells, 38,43 and in senescent cells that present defects in the nuclear lamina. 44 This data suggests a relationship between changes in nuclear distribution of telomeres and alterations of telomere metabolism observed during senescence and immortality.…”

Section: A-type Lamins and Telomere Structure Length And Functionmentioning

confidence: 99%

Loss of A-type lamins and genomic instability

González-Suárez¹,

Redwood²,

Gonzalo³

2009

Cell Cycle

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Research performed in the last few years has revealed important roles for the spatial and temporal organization of the genome on genome function and integrity. A challenge in the field is to determine the molecular mechanisms involved in the organization of genome function. A-type lamins, key structural components of the nucleus, have been implicated in the maintenance of nuclear architecture and chromatin structure. Interestingly, alterations of A-type lamins lead to defects in DNA replication and repair as well as gene transcription and silencing. Elucidating the functions of these proteins is a topical subject since alterations of A-type lamins are associated with a variety of human diseases, ranging from muscular dystrophies and premature aging syndromes to cancer. Here, we discuss novels roles for A-type lamins in the maintenance of telomere structure, length and function as well as in the stabilization of a key DNA damage response factor. These studies support the notion that increased genomic instability due to defects in telomere biology and DNA repair contribute to the pathogenesis of lamin-related diseases.

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Section: A-type Lamins and Telomere Structure Length And Functionmentioning

confidence: 99%

Loss of A-type lamins and genomic instability

González-Suárez¹,

Redwood²,

Gonzalo³

2009

Cell Cycle

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“…For example, in fibroblasts, the activation of c-Myc lead for an abrupt aggregation of telomeres thus leading to the suggestion that this may contribute to chromosomal fusions followed by repeated cycles of breakage-bridge fusions. 23 Soon after these initial descriptions of CIN, it was demonstrated that c-Myc alters the genome at another level. Vafa et al 1 observed that the deregulation of the oncoprotein was accompanied by the induction of reactive ROS and double-stranded DNA breaks, as evidenced by increased TUNEL positivity and the focal accumulation and colocalization of g-H2AX, hMre11, and BRCA1.…”

Section: The "Oncogene From Hell" Reduxmentioning

confidence: 99%

The Ever Expanding Role for c-Myc in Promoting Genomic Instability

Prochownik¹,

Li²

2007

Cell Cycle

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“…5 Mononuclear H cells are the precursors of multinuclear RS cells, [6][7][8][9] and endomitotic multinucleation is associated with disturbed cytokinesis and jumping translocations 10,11 pointing to a severe telomere dysfunction. 12,13 Telomeres are the nucleoprotein complexes at the ends of chromosomes in which a number of specific proteins, either binding telomere proteins directly or a protein complex, termed 'shelterin,' is directly associated with telomeric DNA. [14][15][16] Profound changes in the three-dimensional (3D) nuclear organization of telomeres are the hallmark of the transition from mononuclear H cells to multinuclear RS cells in EBVnegative Hodgkin cell lines and in classical EBV-negative HL.…”

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confidence: 99%

3D Telomere FISH defines LMP1-expressing Reed–Sternberg cells as end-stage cells with telomere-poor ‘ghost' nuclei and very short telomeres

Knecht

Sawan

Lichtensztejn

et al. 2010

Laboratory Investigation

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In Epstein-Barr virus (EBV) negative Hodgkin's cell lines and classical EBV-negative Hodgkin's lymphoma (HL), ReedSternberg cells (RS cells) represent end-stage tumor cells, in which further nuclear division becomes impossible because of sustained telomere loss, shortening and aggregation. However, the three-dimensional (3D) telomere organization in latent membrane protein 1 (LMP1)-expressing RS cells of EBV-associated HL is not known. We performed a 3D telomere analysis after quantitative fluorescent in situ hybridization on 5 mm tissue sections on two LMP1-expressing HL cases and showed highly significant telomere shortening (Po0.0001) and formation of telomere aggregates in RS cells (Po0.0001), when compared with the mononuclear precursor Hodgkin cells (H cells). Telomere-poor or telomere-free 'ghost' nuclei were a regular finding in these RS cells. These nuclei and their telomere content strongly contrasted with the corona of surrounding lymphocytes showing numerous midsized telomere hybridization signals. Both H cells and RS cells of two EBV-negative HL cases analyzed in parallel showed 3D telomere patterns identical to those of LMP1-expressing cases. As a major advance, our 3D nuclear imaging approach allows the visualization of hitherto unknown profound changes in the 3D nuclear telomere organization associated with the transition from LMP1-positive H cells to LMP1-positive RS cells. We conclude that RS cells irrespective of LMP1 expression are end-stage tumor cells in which the extent of their inability to divide further is proportional to the increase of very short telomeres, telomere loss, aggregate formation and the generation of 'ghost' nuclei. Mononuclear H cells are the precursors of multinuclear RS cells, 6-9 and endomitotic multinucleation is associated with disturbed cytokinesis and jumping translocations 10,11 pointing to a severe telomere dysfunction. 12,13 Telomeres are the nucleoprotein complexes at the ends of chromosomes in which a number of specific proteins, either binding telomere proteins directly or a protein complex, termed 'shelterin,' is directly associated with telomeric DNA. [14][15][16] Profound changes in the three-dimensional (3D) nuclear organization of telomeres are the hallmark of the transition from mononuclear H cells to multinuclear RS cells in EBVnegative Hodgkin cell lines and in classical EBV-negative HL. We recently showed that EBV-negative RS cells represent end-stage tumor cells, in which further nuclear division becomes impossible because of sustained telomere loss, shortening and aggregation. 1 However, nothing is known about the 3D telomere organization in LMP1-expressing H and RS cells of EBV-associated Hodgkin's disease (HD). In this study, we document 3D telomere dynamics in LMP1-expressing H and RS cells and show conformity with those observed in EBV-negative HD analyzed in parallel.

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

Cited by 83 publications

References 50 publications

Loss of A-type lamins and genomic instability

Loss of A-type lamins and genomic instability

The Ever Expanding Role for c-Myc in Promoting Genomic Instability

3D Telomere FISH defines LMP1-expressing Reed–Sternberg cells as end-stage cells with telomere-poor ‘ghost' nuclei and very short telomeres

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