Restructuring of Lamina-Associated Domains in Senescence and Cancer

Bellanger, Aurélie; Madsen-Østerbye, Julia; Galigniana, Natalia M.; Collas, Philippe

doi:10.3390/cells11111846

Cited by 12 publications

(11 citation statements)

References 92 publications

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“…Thus, clearly the genome defect is a cause of the pathology. However, we suggest that other prelamin A-dependent events not related to DNA damage response, as for instance remodeling of specific chromatin domains ( Bellanger et al, 2022 ) or recruitment of chromatin binding proteins as BAF, LAP2alpha or HDAC2 ( Lattanzi et al, 2007 ; Mattioli et al, 2008 ; Mattioli et al, 2011 ; Camozzi et al, 2014 ; Loi et al, 2016 ; Mattioli et al, 2018 ) contribute to the onset of organismal ageing when one or more prelamin A forms are stabilized. As a whole, we believe that un-processable prelamin A forms cannot accomplish their main role of sensors of “environmental changes” and timely activators of specific stress responses ( Cenni et al, 2020a ) as any of these functions relies on modulation of prelamin A maturation rate or establishment of transient interactions at the prelamin A-specific C-terminal domain.…”

Section: Discussionmentioning

confidence: 90%

“…Alternatively, recruitment of 53BP1 by non-farnesylated prelamin A could establish a priority in damaged DNA to be repaired. It will be interesting to establish to which damaged sequences is 53BP1targeted in the presence of non-farnesylated prelamin A, if those sequences are within lamina-associated chromatin domains (LADs) ( Robson et al, 2017 ; Bellanger et al, 2022 ; Madsen-Osterbye et al, 2022 ), correspond to the most recently damaged DNA or are they selected by any lamin A/nuclear envelope-related tissue-specific mechanism ( Mattioli et al, 2011 ; Czapiewski et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

Capanni

Schena²,

Giampietro³

et al. 2022

Front. Cell Dev. Biol.

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Lamin A is a main constituent of the nuclear lamina and contributes to nuclear shaping, mechano-signaling transduction and gene regulation, thus affecting major cellular processes such as cell cycle progression and entry into senescence, cellular differentiation and stress response. The role of lamin A in stress response is particularly intriguing, yet not fully elucidated, and involves prelamin A post-translational processing. Here, we propose prelamin A as the tool that allows lamin A plasticity during oxidative stress response and permits timely 53BP1 recruitment to DNA damage foci. We show that while PCNA ubiquitination, p21 decrease and H2AX phosphorylation occur soon after stress induction in the absence of prelamin A, accumulation of non-farnesylated prelamin A follows and triggers recruitment of 53BP1 to lamin A/C complexes. Then, the following prelamin A processing steps causing transient accumulation of farnesylated prelamin A and maturation to lamin A reduce lamin A affinity for 53BP1 and favor its release and localization to DNA damage sites. Consistent with these observations, accumulation of prelamin A forms in cells under basal conditions impairs histone H2AX phosphorylation, PCNA ubiquitination and p21 degradation, thus affecting the early stages of stress response. As a whole, our results are consistent with a physiological function of prelamin A modulation during stress response aimed at timely recruitment/release of 53BP1 and other molecules required for DNA damage repair. In this context, it becomes more obvious how farnesylated prelamin A accumulation to toxic levels alters timing of DNA damage signaling and 53BP1 recruitment, thus contributing to cellular senescence and accelerated organismal aging as observed in progeroid laminopathies.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

Capanni

Schena²,

Giampietro³

et al. 2022

Front. Cell Dev. Biol.

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“…Both the inducement of cellular senescence and cancer are related to the remodeling of the nuclear envelope and the reorganization of heterochromatin. It is well understood that the association of heterochromatin with the nuclear lamina, guaranteed by lamina-associated domains (LADs), is essential for its stabilization [ 83 ]. It also well understood that, during senescence, the modifications in the composition of the nuclear lamina determine changes in epigenetic states and repositioning of LADs, and a loss of peripheral heterochromatin, overlayable to the epigenetic changes occurring in the cancer initiation and progression, supporting the hypothesis that premalignant senescent chromatin changes contribute to oncogenesis [ 84 ].…”

Section: Epigenetic Changes In Aging-related Diseasesmentioning

confidence: 99%

Epigenetic Mechanisms of Aging and Aging-Associated Diseases

Torre

Vecchio

Greco

2023

Cells

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Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At a molecular level, it is marked by the gradual alterations of biomolecules. Indeed, important changes are observed on the DNA, as well as at a protein level, that are influenced by both genetic and environmental parameters. These molecular changes directly contribute to the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders and others aging-related diseases. Additionally, they increase the risk of mortality. Therefore, deciphering the hallmarks of aging represents a possibility for identifying potential druggable targets to attenuate the aging process, and then the age-related comorbidities. Given the link between aging, genetic, and epigenetic alterations, and given the reversible nature of epigenetic mechanisms, the precisely understanding of these factors may provide a potential therapeutic approach for age-related decline and disease. In this review, we center on epigenetic regulatory mechanisms and their aging-associated changes, highlighting their inferences in age-associated diseases.

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“…In addition, polyploidy in giant cancer cells can enlarge chromosome territories [ 109 ]. The ability of polyploidy to relax chromatin via its repositioning from the periphery to the center of the nucleus, as well as to alter LADs and TADs geometry, is also characteristic of cancer cells [ 109 , 110 ]. Thus, both c-Myc and polyploidy can reposition chromatin from the nuclear periphery to the inner part of the nucleus, promoting its relaxation ( Figure 2 ).…”

Section: Myc and Polyploidy Promote Chromatin Openingmentioning

confidence: 99%

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

Anatskaya

Vinogradov

2022

IJMS

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Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases.

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Restructuring of Lamina-Associated Domains in Senescence and Cancer

Cited by 12 publications

References 92 publications

The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

The role of prelamin A post-translational maturation in stress response and 53BP1 recruitment

Epigenetic Mechanisms of Aging and Aging-Associated Diseases

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

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