A function for ataxia telangiectasia and Rad3-related (ATR) kinase in cytokinetic abscission

Luessing, Janna; Okowa, Chituru C; Brennan, Emer; Voisin, Muriel; Lowndes, Noel F.

doi:10.1016/j.isci.2022.104536

Cited by 2 publications

(2 citation statements)

References 51 publications

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“…1, F and G ), which could be due to minor impairment of DNA replication/repair or defective chromosome segregation. A tempting hypothesis is that DRF1 may modulate the timing of abscission at the end of the cell cycle, a non-essential process in which CDC7 was recently shown to be involved and that, if impaired, can lead to micronucleated cells ( Luessing et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks

Göder,

Maric,

Rainey

et al. 2024

Journal of Cell Biology

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CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient in either DBF4 or DRF1: these cells are viable but present signs of genomic instability, indicating that both can independently support CDC7 for bulk DNA replication. Nonetheless, DBF4-deficient cells show altered replication efficiency, partial deficiency in MCM helicase phosphorylation, and alterations in the replication timing of discrete genomic regions. Notably, we find that CDC7 function at replication forks is entirely dependent on DBF4 and not on DRF1. Thus, DBF4 is the primary regulator of CDC7 activity, mediating most of its functions in unperturbed DNA replication and upon replication interference.

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Section: Resultsmentioning

confidence: 99%

DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks

Göder,

Maric,

Rainey

et al. 2024

Journal of Cell Biology

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“…24 Anomalies in CHMP1B ubiquitination hamper vesicle trafficking of VEGFR2 (vascular endothelial growth factor receptor 2), leading to congenital heart disease. 25 Although most research on CHMP4C has centered on cytokinetic abscission and virus budding, 14,[26][27][28] we have previously shown that CHMP4C is a risk gene for inherited dilated cardiomyopathy, operating primarily through autophagy regulation, 17 a critical event in cardiovascular diseases. 29,30 Here, our data confirmed that CHMP4C silencing notably aggravated TACinduced cardiac hypertrophy and phenylephrine-induced cardiomyocyte dysfunction.…”

Section: Discussionmentioning

confidence: 99%

ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR

Liu,

Xie,

Tian

et al. 2023

Hypertension

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BACKGROUND: Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated degradation of membrane proteins, is associated with cardiac hypertrophy progression. CHMP4C (charged multivesicular body protein 4C), a critical constituent of multivesicular bodies, is involved in cellular trafficking and signaling. However, the specific role of CHMP4C in the progression of cardiac hypertrophy remains largely unknown. METHODS: Mouse models with CHMP4C knockout or cardiadc-specific overexpression were subjected to transverse aortic constriction surgery for 4 weeks. Cardiac morphology and function were assessed through histological staining and echocardiography. Confocal imaging and coimmunoprecipitation assays were performed to identify the direct target of CHMP4C. An EGFR (epidermal growth factor receptor) inhibitor was administrated to determine whether effects of CHMP4C on cardiac hypertrophy were EGFR dependent. RESULTS: CHMP4C was significantly upregulated in both pressure-overloaded mice and spontaneously hypertensive rats. Compared with wild-type mice, CHMP4C deficiency exacerbated transverse aortic constriction–induced cardiac hypertrophy, whereas CHMP4C overexpression in cardiomyocytes attenuated cardiac dysfunction. Mechanistically, the effect of CHMP4C on cardiac hypertrophy relied on the EGFR signaling pathway. Fluorescent staining and coimmunoprecipitation assays confirmed that CHMP4C interacts directly with EGFR and promotes lysosome-mediated degradation of activated EGFR, thus attenuating cardiac hypertrophy. Notably, an EGFR inhibitor canertinib counteracted the exacerbation of cardiac hypertrophy induced by CHMP4C knockdown in vitro and in vivo. CONCLUSIONS: CHMP4C represses cardiac hypertrophy by modulating lysosomal degradation of EGFR and is a potential therapeutic candidate for cardiac hypertrophy.

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A function for ataxia telangiectasia and Rad3-related (ATR) kinase in cytokinetic abscission

Cited by 2 publications

References 51 publications

DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks

DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks

ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR

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