Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

Etourneaud, Laure; Moussa, Angela; Rass, Emilie; Genet, Diane; Willaume, Simon; Chabance-Okumura, Caroline; Wanschoor, Paul; Picotto, Julien; Thézé, Benoît; Dépagne, Jordane; Veaute, Xavier; Dizet, Eléa; Busso, Didier; Barascu, Aurélia; Irbah, Lamya; Kortulewski, Thierry; Campalans, Anna; Chalony, Catherine Le; Zinn‐Justin, Sophie; Scully, Ralph; Pennarun, Gaëlle; Bertrand, Pascale

doi:10.1126/sciadv.abb3799

Cited by 26 publications

(30 citation statements)

References 77 publications

(119 reference statements)

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“…In that context, we investigated how prelamin A accumulation interferes with lamin A/C-53BP1 binding and formation of 53BP1 foci at DNA damage sites. PLA experiments confirmed the interaction between lamin A/C and 53BP1, supporting direct binding between the two proteins (Etourneaud et al, 2021). Our results show that, under basal conditions, the presence of non-farnesylated prelamin A does not affect lamin A/C-53BP1 interaction.…”

Section: Figuresupporting

confidence: 77%

“…Another interaction involving lamin A/C during DNA damage response is the one with 53BP1, a protein recruited to DNA damage sites that in turn contributes to recruitment of other repair factors ( Etourneaud et al, 2021 ; Paiano et al, 2021 ). Altered nuclear recruitment of 53BP1 has been observed in HGPS cells and ascribed to the dominant negative effect of progerin (a truncated form of farnesylated prelamin A) ( Gonzalez-Suarez et al, 2011 ; Kreienkamp et al, 2016 ).…”

Section: Introductionmentioning

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: Figuresupporting

confidence: 77%

Section: Introductionmentioning

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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“…Unlike the previously reported mechanically-induced proliferation through mechanosensitive channels [47] , the altered proliferation and DNA damage response observed here is a result of a transient deformation which have not been reported before. Cellular lamin B1 expression was previously found to associate with telomere and chromosome instability [48,49] , recruitment of DNA damage repair proteins [50] , and cellular senescence [51] . However, similar to the resilience to deformation, the elevated lamin B1 level reverted with time in our study while the enhanced proliferation could remain in the selected cancer cells for more than 2 months (Figure.…”

Section: Discussionmentioning

confidence: 99%

Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance

Jiang

Lim

Xiao

et al. 2022

Preprint

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Cancer cells derived from secondary tumors can form new distant metastases more efficiently as compared to their primary tumor counterparts. This is partially due to the unfavorable microenvironments encountered by metastasizing cancer cells that result in the survival of a more metastatic phenotype from the original population. However, it is unclear how cancer cells may acquire such metastatic competency after overcoming deleterious mechanical stresses. Here, by forcing cancer cells to flow through small capillary-sized constrictions, we demonstrate that mechanical deformation can select a tumor cell subpopulation that exhibits resilience to mechanical squeezing-induced cell death. Transcriptomic profiling reveals up-regulated proliferation and DNA damage response pathways in this subpopulation, which are further translated into a more proliferative and chemotherapy-resistant phenotype. Our results highlight a potential link between the microenvironmental physical barriers and the enhanced malignancy of metastasizing cancer cells which may potentially be utilized for novel therapeutic strategies in preventing the metastatic spread of cancer cells.

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“…In fact, while increased lamin B1 levels are linked to ADLD, reduced lamin B1 amount is associated with ageing processes. On the other hand, depending on the trigger, cellular senescence can be also linked to increased lamin B1 amount [ 30 ], a condition recently linked to sequestering of the DNA damage repair factor 53BP1 and altered DNA damage response [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

Evangelisti

Rusciano

Mongiorgi

et al. 2022

Cell. Mol. Life Sci.

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B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer. Graphical abstract

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Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

Cited by 26 publications

References 77 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

Deleterious Mechanical Deformation Selects Mechanoresilient Cancer Cells with Enhanced Proliferation and Chemoresistance

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

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