Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation

Aix, Esther; Gutiérrez-Gutiérrez, Óscar; Sánchez-Ferrer, Carlota; Aguado, Tania; Flores, Ignacio

doi:10.1084/jem.2137oia57

Cited by 11 publications

(16 citation statements)

References 50 publications

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“…Excess DNA damage in post-natal hearts has been associated with CM binucleation (Aix, et al, 2016 Repair factor KD further increased the fraction of '4N' cells (vs '2N'; Fig.4A-iv, S3A), in agreement with trends for blebbistatin-treated hearts ( Fig.1G) and with mitotic arrest. LMNA KD had all of the same effects, consistent with a role in repair factor retention in nuclei, and consistent also with a late checkpoint, KD showed more DNA damage per DNA in '4N' cells relative to siCtrl cells ( Fig.S3B).…”

Section: Loss Of Repair Factors or Lmna: Dna Damage Binucleation And Msupporting

confidence: 75%

“…A combination of factors ('GFP-Combo') rescued the excess damage while one repair factor had no effect on its own (53BP1) even on the ruptured nuclei. Rescue of DNA damage again suppressed the fraction of Since cardiac telomere attrition has been implicated in CM binucleation (Aix, et al, 2016) as well as in cardiomyopathies and heart failure , we assessed rupture-associated telomere shortening as a more localized form of DNA damage (Fig.4D). U2OS osteosarcoma cells with ruptured nuclei (cytoplasmic anti-KU80) showed lower total intensity of TRF1 (telomeric repeat-binding factor-1 as an mCherry fusion; Fig.4E-i) and smaller TRF1 foci size ( Fig.4E-ii), as well as higher γH2AX in these LMNA KD cells.…”

Section: Loss Of Repair Factors or Lmna: Dna Damage Binucleation And Mmentioning

confidence: 99%

“…cardiac arrest or cardiomyopathy treatment Page 3 of 29 from proliferation to senescence in post-natal hearts (Puente, et al, 2014). DNA damage is also implicated in telomere attrition and binucleation of CMs that signal irreversible exit from cell cycle (Aix, et al, 2016). We postulated embryonic hearts with rapidly tunable mechanics could prove useful as a tissue model for clarifying protein-level mechanosensing mechanisms in vivo that could be studied thoroughly in vitro with many cell types.…”

Section: Introductionmentioning

confidence: 99%

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Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

Cho

Vashisth

Abbas

et al. 2019

Preprint

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Whether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear.Here, acute perturbations (~1hr) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. Embryonic hearts, differentiated iPS-cells, and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrix-metalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility is seen to minimize DNA damage. Lamin-A is thus stress-stabilized to mechano-protect the genome.(137 words)

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Section: Loss Of Repair Factors or Lmna: Dna Damage Binucleation And Msupporting

confidence: 75%

Section: Loss Of Repair Factors or Lmna: Dna Damage Binucleation And Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

Cho

Vashisth

Abbas

et al. 2019

Preprint

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“…Second, telomere biology diseases are usually difficult to model in mice because of differences in telomere length and telomerase expression between mice and humans. Mice that lack telomerase exhibited short telomeres only after three or four generations (G3/G4) of intracrosses (12,13). However, mice with a telomerase haploinsufficiency and a deficient shelterin complex exhibited telomere dysfunction and DC features in a single generation (G1) (14).…”

Section: Introductionmentioning

confidence: 99%

Germline mutation of MDM4 , a major p53 regulator, in a familial syndrome of defective telomere maintenance

et al. 2020

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Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.

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“…Several reports have demonstrated increased cell cycle activity by ectopic gene expression in proliferative neonatal mammalian cardiomyocytes (36-38), but fewer have shown cell cycle re-entry in senescent adult mammalian cardiomyocytes. Of factors known to be sufficient for induction of DNA synthesis in adult mammalian cardiomyocytes, strong evidence exists for E2F transcription factors (31,39), thus they are of interest to the pressing question of how adult mouse cardiomyocytes can be artificially stimulated to proliferate (40,41). E2F transcription factors 1-3 are known activators of the cell cycle and are negatively regulated through sequestration by pocket proteins, such as retinoblastoma protein (RB), p107, and p130 (42).…”

Section: Discussionmentioning

confidence: 99%

Defined factors to reactivate cell cycle activity in adult mouse cardiomyocytes

Judd

Lovas

Huang

2019

Preprint

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Adult mammalian cardiomyocytes exit the cell cycle during the neonatal period, commensurate with the loss of regenerative capacity in adult mammalian hearts. We established conditions for long-term culture of adult mouse cardiomyocytes that are genetically labeled with fluorescence. This technique permits reliable analyses of proliferation of pre-existing cardiomyocytes without complications from cardiomyocyte marker expression loss due to dedifferentiation or significant contribution from cardiac progenitor cell expansion and differentiation in culture.Using this system, we took a candidate gene approach to screen for fetal-specific proliferative gene programs that can induce proliferation of adult mouse cardiomyocytes. Using pooled gene delivery and subtractive gene elimination, we identified a novel functional interaction between E2f Transcription Factor 2 (E2f2) and Brain Expressed X-Linked (Bex)/Transcription elongation factor A-like (Tceal) superfamily members Bex1 and Tceal8. Specifically, Bex1 and Tceal8 both preserved cell viability during E2f2-induced cell cycle re-entry. Although Tceal8 inhibited E2f2-induced S-phase re-entry, Bex1 facilitated DNA synthesis while inhibiting cell death. In sum, our study provides a valuable method for adult cardiomyocyte proliferation research and suggests that Bex family proteins may function in modulating cell proliferation and death decisions during cardiomyocyte development and maturation.Real-time PCR showed that expression of endogenous positive cell cycle regulators Cyclin A2 and Cyclin E were induced by ectopic E2f2 expression, in agreement with

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Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation

Cited by 11 publications

References 50 publications

Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

Germline mutation of MDM4 , a major p53 regulator, in a familial syndrome of defective telomere maintenance

Defined factors to reactivate cell cycle activity in adult mouse cardiomyocytes

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