The higher-order structure in the cells nucleus as the structural basis of the post-mitotic state

Aranda‐Anzaldo, Armando; Dent, Myrna A. R.; Martínez-Gómez, Alejandro

doi:10.1016/j.pbiomolbio.2014.02.002

Cited by 8 publications

(9 citation statements)

References 102 publications

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“…13 Similarly, it is also possible to infer that in prostate tissues a decrease in the interaction between NM proteins and MAR sequences increases loop dimensions, and thus enhancing variations in gene positioning and transcription. In agreement with our results, Aranda-Anzaldo et al 44 recently presented a model that correlates the stochastic stabilization of the chromatin higher-order structure with cellular differentiation. Specifically, they proposed that in highly proliferating cells, chromosome regions are organized in long supercoiled DNA loops that are fastened only to few NM proteins, giving rise to a loose and unstable structure.…”

Section: Discussionsupporting

confidence: 93%

“…Similarly, it is also possible to infer that in prostate tissues a decrease in the interaction between NM proteins and MAR sequences increases loop dimensions, and thus enhancing variations in gene positioning and transcription. In agreement with our results, Aranda‐Anzaldo et al . recently presented a model that correlates the stochastic stabilization of the chromatin higher‐order structure with cellular differentiation.…”

Section: Discussionsupporting

confidence: 93%

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Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP‐1: New player in tumor progression

Barboro

Ferrari

Capaia

et al. 2015

Intl Journal of Cancer

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Prostate cancer (PCa) displays infrequent point mutations, whereas genomic rearrangements are highly prevalent. In eukaryotes, the genome is compartmentalized into chromatin loop domains by the attachment to the nuclear matrix (NM), and it has been demonstrated that several recombination hot spots are situated at the base of loops. Here, we have characterized the binding between NM proteins and matrix attachment regions (MARs) in PCa. Nontumor and 44 PCa tissues were analyzed. More aggressive tumors were characterized by an increase in the complexity of the NM protein patterns that was synchronous with a decrease in the number of proteins binding the MAR sequences. PARP-1 was the protein that showed the most evident changes. The expression of the PARP-1 associated with NM increased and it was dependent on tumor aggressiveness. Immunohistochemical analysis showed that the protein was significantly overexpressed in tumor cells. To explore the role of PARP-1 in PCa progression, PCa cells were treated with the PARP inhibitor, ABT-888. In androgen-independent PC3 cells, PARP inhibition significantly decreased cell viability, migration, invasion, chromatin loop dimensions and histone acetylation. Collectively, our study provides evidence that MAR-binding proteins are involved in the development and progression of PCa. PARP could play a key role in the compartmentalization of chromatin and in the development of the more aggressive phenotype. Thus, PARP can no longer be viewed only as an enzyme involved in DNA repair, but that its role in chromatin modulation could provide the basis for a new therapeutic approach to the treatment of PCa.Although significant advancements have been made in the understanding of the molecular events responsible for the development and progression of prostate cancer (PCa), this tumor remains the most frequently diagnosed among males in economically developed countries.1 The pathogenesis of this cancer is complex; it has an extremely heterogeneous clinical behavior and, different from many other cancers, the events associated with its initiation and progression remain poorly understood.2 Therefore, an improved comprehension of the molecular aspects of PCa progression could help to detect new diagnostic and prognostic markers and define new therapeutic strategies.PCa displays infrequent point mutations, whereas genomic rearrangements are highly prevalent.3 Recently, Baca et al. 4sequenced the whole genomes of 57 PCa cases and identified abundant DNA translocations and deletions. These large-scale chromosomal rearrangements arise through a single and highly interdependent process, rather than through independent multiple steps. The authors coined the term "chromoplexy" to describe this phenomenon of complex genome restructuring. It is known that in eukaryotes, the genome is compartmentalized into chromatin loop domains by the attachment to nuclear matrix (NM). 5 The interactions of chromatin with the NM are a dynamic event that is functionally dependent, 6 and occur via noncoding AT-rich DNA se...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP‐1: New player in tumor progression

Barboro

Ferrari

Capaia

et al. 2015

Intl Journal of Cancer

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“…This is in part due to tensile forces of the actin cytoskeleton that use physical linkages on the outer envelope. These forces are countered by chromatin condensation, acting through chromatin-envelope tethers and chromatin-matrix attachments [ 1 , 28 ], each force pulling in opposite direction as they converge on the nuclear envelope [ 2 ]. These forces are paired with the compressive action of microtubules and entropic force of the DNA polymer itself, together creating a balanced web of counteracting forces upon the nuclear envelope.…”

Section: Resultsmentioning

confidence: 99%

Condensins are Required for Maintenance of Nuclear Architecture

George

Bozler

Nguyen

et al. 2014

Cells

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The 3-dimensional spatial organization of eukaryotic genomes is important for regulation of gene expression as well as DNA damage repair. It has been proposed that one basic biophysical property of all nuclei is that interphase chromatin must be kept in a condensed prestressed state in order to prevent entropic pressure of the DNA polymer from expanding and disrupting the nuclear envelope. Although many factors can contribute to specific organizational states to compact chromatin, the mechanisms through which such interphase chromatin compaction is maintained are not clearly understood. Condensin proteins are known to exert compaction forces on chromosomes in anticipation of mitosis, but it is not known whether condensins also function to maintain interphase prestressed chromatin states. Here we show that RNAi depletion of the N-CAP-H2, N-CAP-D3 and SMC2 subunits of human condensin II leads to dramatic disruption of nuclear architecture and nuclear size. This is consistent with the idea that condensin mediated chromatin compaction contributes significantly to the prestressed condensed state of the interphase nucleus, and when such compaction forces are disrupted nuclear size and shape change due to chromatin expansion.

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“…The fact that mechanical force directly applied to the nuclear DNA is able to disaggregate the NM (Maya‐Mendoza et al, ) strongly suggests that DNA has a structural role in sustaining the integrity of the NM compartment, and this has led to propose a model of the NHOS based on the architectural engineering principle of structural tensegrity (Aranda‐Anzaldo, ; Aranda‐Anzaldo, Dent, & Martínez‐Gómez, ). This principle is applied for building lightweight but highly resistant and resilient structures, and there are many examples showing that it participates in the structural organization of cells (Ingber, Wang, & Stamenovic, ).…”

Section: A Structural Explanation For the Postmitotic State In Neuronsmentioning

confidence: 99%

“…The process of karyokinesis necessarily requires the destabilization of the NHOS and in vivo this is achieved by metabolic energy in the form of specific phosphorylation of NM components (such as lamins) for their disassembly (Vlcek, Dechat, & Foisner, ). However, such phosphorylations have no effect upon DNA that may keep the NM proteins assembled by performing in a similar fashion to the cables in a suspension bridge that keep the deck's segments into place (Aranda‐Anzaldo, ; Aranda‐Anzaldo, Dent & Martínez‐Gómez, ). Thus given that cellular metabolic energy is limited, when the stability of the NHOS goes beyond a certain threshold it becomes an insurmountable energy barrier for karyokinesis (and as such for mitosis), since the energy input (in the form of targeted phosphorylation) is not enough for destabilizing the NHOS and so the cell becomes stably postmitotic.…”

Section: A Structural Explanation For the Postmitotic State In Neuronsmentioning

confidence: 99%

Lessons we can learn from neurons to make cancer cells quiescent

Dent

Aranda‐Anzaldo

2019

J of Neuroscience Research

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Cancer is a major concern for contemporary societies. However, the incidence of cancer is unevenly distributed among tissues and cell types. In particular, the evidence indicates that neurons are absolutely resistant to cancer and this is commonly explained on the basis of the known postmitotic state of neurons. The dominant paradigm on cancer understands this problem as a disease caused by mutations in cellular genes that result in unrestrained cell proliferation and eventually in tissue invasion and metastasis. However, the evidence also shows that mutations and gross chromosomal anomalies are common in functional neurons that nevertheless do not become neoplastic. This fact suggests that in the real nonexperimental setting mutations per se are not enough for inducing carcinogenesis but also that the postmitotic state of neurons is not genetically controlled or determined, otherwise there should be reports of spontaneously transformed neurons. Here we discuss the evidence that the postmitotic state of neurons has a structural basis on the high stability of their nuclear higher order structure that performs like an absolute tumor suppressor.We also discuss evidence that it is possible to induce a similar structural postmitotic state in nonneural cell types as a practical strategy for stopping or reducing the progression of cancer. K E Y W O R D SDNA loops, DNA replication, nuclear higher order structure, nuclear matrix, postmitotic state, somatic mutation, tensegrity

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The higher-order structure in the cells nucleus as the structural basis of the post-mitotic state

Cited by 8 publications

References 102 publications

Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP‐1: New player in tumor progression

Expression of nuclear matrix proteins binding matrix attachment regions in prostate cancer. PARP‐1: New player in tumor progression

Condensins are Required for Maintenance of Nuclear Architecture

Lessons we can learn from neurons to make cancer cells quiescent

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