Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity

Background Chronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries. Methods and Results Partial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2). Conclusions IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis.

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Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Circulation Research ◽

10.1161/circresaha.107.158626 ◽

2008 ◽

Vol 102 (2) ◽

pp. 201-208 ◽

Cited By ~ 114

Author(s):

Karl E. Herbert ◽

Yogita Mistry ◽

Richard Hastings ◽

Toryn Poolman ◽

Laura Niklason ◽

...

Keyword(s):

Dna Damage ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Cellular Senescence ◽

Oxidative Dna Damage ◽

Muscle Cells

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Dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest

Genomics ◽

10.1016/j.ygeno.2019.07.020 ◽

2020 ◽

Vol 112 (2) ◽

pp. 1309-1317 ◽

Cited By ~ 1

Author(s):

Zhen Zhao ◽

Qiongye Dong ◽

Xuehui Liu ◽

Lei Wei ◽

Liyang Liu ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Transcriptome Profiling ◽

Cycle Arrest

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Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage

Biomedicines ◽

10.3390/biomedicines8100397 ◽

2020 ◽

Vol 8 (10) ◽

pp. 397

Author(s):

Cheuk Yiu Tenny Chung ◽

Paulisally Hau Yi Lo ◽

Kenneth Ka Ho Lee

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Dna Damage ◽

Gamma Irradiation ◽

Cellular Senescence ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Embryonic Stem ◽

Cycle Progression ◽

Cycle Regulation

BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

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Erratum to “Dysfunction of lamin A triggers a DNA damage response and cellular senescence” [DNA Repair 5 (2006) 286–289]

DNA Repair ◽

10.1016/j.dnarep.2006.02.006 ◽

2006 ◽

Vol 5 (5) ◽

pp. 649

Author(s):

Susan P. Lees-Miller

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Cellular Senescence ◽

Lamin A ◽

Damage Response

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Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00175.2012 ◽

2012 ◽

Vol 303 (7) ◽

pp. L557-L566 ◽

Cited By ~ 70

Author(s):

Hongwei Yao ◽

Irfan Rahman

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Cellular Senescence ◽

Premature Aging ◽

Epigenetic Mechanism ◽

Histone Deacetylase 2 ◽

Damage Response

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.

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BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

Molecular and Cellular Biology ◽

10.1128/mcb.01744-12 ◽

2013 ◽

Vol 33 (9) ◽

pp. 1819-1829 ◽

Cited By ~ 28

Author(s):

Zhigang Tu ◽

Xinying Zhuang ◽

Yong-Gang Yao ◽

Rugang Zhang

Keyword(s):

Dna Damage ◽

Molecular Mechanism ◽

Chromatin Remodeling ◽

Cellular Senescence ◽

Chromatin Immunoprecipitation ◽

Tumor Suppression ◽

Gene Promoters ◽

Independent Manner ◽

Oncogenic Ras ◽

Suppression Mechanism

Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of s enescence- a ssociated h eterochromatin f oci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21 CIP1 , and p16 INK4a , but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.

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