DNA damage response links calpain to cellular senescence

Demarchi, Francesca; Cataldo, Francesca; Bertoli, Cosetta; Schneider, Claudio

doi:10.4161/cc.9.4.10637

Cited by 16 publications

(14 citation statements)

References 16 publications

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“…Over 100 diverse calpain targets have been identified to date, indicating a wide role for calpains in mediating signal transduction processes. Calpain proteases are probably involved in the DNA damage response initiated at the start of cellular senescence, because depletion of the CAPSN1 regulatory subunit diminished senescence markers including phosphorylated histone H2AX in cells induced to undergo senescence through oncogenic, radiation or chemical stress (Demarchi et al, 2010). Our findings here indicate that calpain activity is increased in cells undergoing senescence and that Tiam1 is likely to be a calpain target in cells under those conditions.…”

Section: Discussionsupporting

confidence: 54%

“…Several signaling pathways and proteases have been reported to be involved in the degradation of Tiam1 protein, in particular activation of calcium-dependent calpain proteases (Qi et al, 2001;Woodcock et al, 2009). Induction of senescence in various cell types triggers a DNA damage response that then triggers activation of calpain proteases (Demarchi et al, 2010). In order to explore whether calpains might be involved in Tiam1 downregulation in senescent cells, we tested whether calpain activation was increased in cells undergoing induced senescence (supplementary material Fig.…”

Section: Rmfs Undergo Stress-induced Senescencementioning

confidence: 99%

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Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Liu

Chase

et al. 2012

Journal of Cell Science

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SummaryThe tumor microenvironment undergoes changes concurrent with neoplastic progression. Cancer incidence increases with aging and is associated with tissue accumulation of senescent cells. Senescent fibroblasts are thought to contribute to tumor development in aging tissues. We have shown that fibroblasts deficient in the Rac exchange factor Tiam1 promote invasion and metastasis of associated epithelial tumor cells. Here, we use a three-dimensional culture model of cellular invasiveness to outline several steps underlying this effect. We find that stress-induced senescence induces decreased fibroblast Tiam1 protein levels and increased osteopontin levels, and that senescent fibroblast lysates induce Tiam1 protein degradation in a calcium-and calpain-dependent fashion. Changes in fibroblast Tiam1 protein levels induce converse changes in osteopontin mRNA and protein. Senescent fibroblasts induce increased invasion and migration in co-cultured mammary epithelial cells. These effects in epithelial cells are ameliorated by either increasing fibroblast Tiam1 or decreasing fibroblast osteopontin. Finally, in seeded cell migration assays we find that either senescent or Tiam1-deficient fibroblasts induce increased epithelial cell migration that is dependent on fibroblast secretion of osteopontin. These findings indicate that one mechanism by which senescent fibroblasts promote neoplastic progression in associated tumors is through degradation of fibroblast Tiam1 protein and the consequent increase in secretion of osteopontin by fibroblasts.

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Section: Discussionsupporting

confidence: 54%

Section: Rmfs Undergo Stress-induced Senescencementioning

confidence: 99%

Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Liu

Chase

et al. 2012

Journal of Cell Science

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“…In addition, a large amount of evidence is showing that calpains mediate the proteolytic cleavage of substrates specifically involved in various cellular processes during differentiation and cell death. Thus, calpains are also involved in senescence [38]. Furthermore, calpains positively modulate autophagy to limit the accumulation of damaged organelles and proteins, and then cleave essential autophagic…”

Section: Page 19 Of 59mentioning

confidence: 99%

Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

Schnekenburger

Grandjenette

Ghelfi

et al. 2011

Biochemical Pharmacology

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Sustained exposure to the DNA demethylating agent; 2'-deoxy-5-azacytidine; leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation; senescence; and autophagy. Biochemical Pharmacology, Elsevier, 2010, 81 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 59A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractIn addition to its demethylating properties, 5-aza-2'-deoxycytidine (DAC) induces cell cycle arrest, differentiation, cell sensitization to chemotherapy, and cell death. However, the mechanisms by which DAC induces antiproliferation via these processes and how they are interconnected remain unclear. In this study, we found that a clinically relevant concentration of DAC triggered erythroid and megakaryocytic differentiation in the human chronic myeloid leukemia (CML) K-562 and MEG-01 cell lines, respectively. In addition, cells showed a marked increase in cell size in both cell lines and a more adhesive cell profile for MEG-01.Furthermore, DAC treatment induced cellular senescence and autophagy as shown by β-galactosidase staining and by autophagosome formation, respectively. After prolonged DAC treatment, phosphatidyl serine exposure, nuclear morphology analysis, and caspase cleavage revealed an activation of mitochondrial-dependent apoptosis in CML cells. This activation was accompanied by a decrease of anti-apoptotic proteins and an increase of calpain activity.Finally, we showed that combinatory treatment of relatively resistant CML with DAC and either conventional apoptotic inducers or with an histone deacetylase inhibitor increased synergistically apoptosis. We therefore conclude that induction of differentiation, senescence, and autophagy in CML are a key in cell sensitization and DAC-induced apoptosis.

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“…2f). Interestingly, CAPNS1 depletion, obtained upon infection with an adeno-associated virus (AAV) vector expressing a short hairpin targeting CAPNS1 (16), is coupled to a reduction of the USP1 protein level also in this cellular model (Fig. 2f).…”

Section: Usp1 Interacts With Capns1mentioning

confidence: 99%

CAPNS1 Regulates USP1 Stability and Maintenance of Genome Integrity

Cataldo

Peche

Klaric

et al. 2013

Molecular and Cellular Biology

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cCalpains regulate a wide spectrum of biological functions, including migration, adhesion, apoptosis, secretion, and autophagy, through the modulating cleavage of specific substrates. Ubiquitous microcalpain (-calpain) and millicalpain (m-calpain) are heterodimers composed of catalytic subunits encoded, respectively, by CAPN1 and CAPN2 and a regulatory subunit encoded by CAPNS1. Here we show that calpain is required for the stability of the deubiquitinating enzyme USP1 in several cell lines. USP1 modulates DNA replication polymerase choice and repair by deubiquitinating PCNA. The ubiquitinated form of the USP1 substrate PCNA is stabilized in CAPNS1-depleted U2OS cells and mouse embryonic fibroblasts (MEFs), favoring polymeraseloading on chromatin and increased mutagenesis. USP1 degradation directed by the cell cycle regulator APC/C cdh1 , which marks USP1 for destruction in the G 1 phase, is upregulated in CAPNS1-depleted cells. USP1 stability can be rescued upon forced expression of calpain-activated Cdk5/p25, previously reported as a cdh1 repressor. These data suggest that calpain stabilizes USP1 by activating Cdk5, which in turn inhibits cdh1 and, consequently, USP1 degradation. Altogether these findings point to a connection between the calpain system and the ubiquitin pathway in the regulation of DNA damage response and place calpain at the interface between cell cycle modulation and DNA repair. Calpains regulate a wide spectrum of biological functions, including migration, adhesion, apoptosis, secretion, and autophagy through the modulated cleavage of specific substrates (reviewed in references 1-3). Ubiquitous microcalpain (-calpain) and millicalpain (m-calpain) are heterodimers composed of a catalytic subunit encoded, respectively, by CAPN1 and CAPN2 and a regulatory subunit encoded by CAPNS1. Both -calpain and mcalpain are negatively modulated by calpastatin. By a proteomic approach, we identified USP1 deubiquitinase as a CAPNS1-interacting protein. USP1 is a key modulator of DNA repair, partly through deubiquitination of its known targets FANCD2 (4, 5) and PCNA (6). Usp1 knockout (KO) mice have a severe phenotype and die soon after birth (7). Usp1 Ϫ/Ϫ cells are defective in FANCD2 focus formation and are hypersensitive to DNA damage (8). PCNA ubiquitination is higher in USP1-depleted cells than in control cells, thus leading to recruitment of error-prone, translesion DNA synthesis (TLS) polymerases and the consequent increase in mutation rate (6). USP1 promotes inhibitor of DNA binding (ID) protein stability and stem cell-like characteristics in osteosarcoma and is required for normal skeletogenesis (9). Interestingly, mice lacking CAPNS1 in cells of the osteoblast lineage are defective in bone development and remodeling in vivo (10).UV light irradiation activates hUSP1 autocleavage at glycines 670 and 671, inducing its subsequent proteasomal degradation (6). USP1 mutants with mutation in the catalytic cysteine 90 or in the autocleavage sites are more stable but can still be degraded in the cell (5), s...

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DNA damage response links calpain to cellular senescence

Cited by 16 publications

References 16 publications

Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

CAPNS1 Regulates USP1 Stability and Maintenance of Genome Integrity

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