The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype
Open accessAbstract
Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism typified by stable proliferative arrest, a persistent DNA damage response, and the senescence-associated secretory phenotype (SASP), which helps to maintain the senescent state and triggers bystander senescence in a paracrine fashion. Here, we demonstrate that the tumor suppressive histone variant macroH2A1 is a critical component of the positive feedback loop that maintains SASP gene expression and triggers the induction of paracrine senescence. MacroH2A1 undergoes dramatic genome-wide relocalization during OIS, including its removal from SASP gene chromatin. The removal of macroH2A1 from SASP genes results from a negative feedback loop activated by SASP-mediated endoplasmic reticulum (ER) stress. ER stress leads to increased reactive oxygen species and persistent DNA damage response including activation of ATM, which mediates removal macroH2A1 from SASP genes. Together, our findings indicate that macroH2A1 is a critical control point for the regulation of SASP gene expression during senescence.
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In the citing paper
“ATM was found to regulate expression of SASP genes indirectly by mediating the removal of the histone variant macroH2A1.1 from SASP genes in response to DNA damage and oncogenic stress87”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [87]
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In the citing paper
“Other epigenetic regulators, such as macroH2A1, high mobility group box 2 (HMGB2), mixed‐lineage leukemia 1 (MLL1) and bromodomain‐containing protein 4 (BRD4), have been demonstrated as regulators of SASP factor gene expression in response to DNA damage.52, 53, 54, 55”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [52]
In the citing paper
“These factors are primarily proinflammatory and act in a paracrine and autocrine manner [44,45], although immunosuppressive mediators have also been identified as part of SASP [46,47].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [45]
In the citing paper
“The SASP consists of a noxious secretome comprised of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins (24–27).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [25]
In the citing paper
“Upregulation of SASP genes is balanced by a negative feedback loop whereby macroH2A1 activates DDR signaling that leads to macroH2A1 removal from the chromatin of SASP genes, thus reducing their expression [168].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [168]
In the citing paper
“Active ATM triggers the removal from SASP genes of the histone variant macroH2A1, leading to inhibition of their transcription and reduction in ER stress [168].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [168]
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Citations
Cites
Signal integration in the endoplasmic reticulum unfolded protein response
Ron, D., & Walter, P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2199 · Cited by 6,431
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 1×
“Instead, oncogene-induced senescence (OIS), an important tumor suppressivemechanism, is triggered, leading to a stable proliferative arrest (Gorgoulis and Halazonetis, 2010; Serrano et al., 1997).”
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
The unfolded protein response: controlling cell fate decisions under ER stress and beyond
Hetz, C. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3270 · Cited by 4,223
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · cited 1×
“In aging or immunocompromised individuals, SASP fails to lead to the clearance of senescent cells that may contribute to a persistent inflammatory state (Baker et al., 2011; Schmitt, 2007).”
Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes
Land, H., Parada, L. F., & Weinberg, R. A. (1983) · Nature · doi:10.1038/304596a0 · Cited by 2,804
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379 · cited 1×
“…in a variety of physiological and pathological processes including senescence, tumor suppression, inhibiting proliferation, and inhibiting stem cell reprogramming (Cantariño et al., 2013; Creppe et al., 2012; Gamble and Kraus, 2010; Kreiling et al., 2011; Novikov et al., 2011; Sporn et al., 2009).”
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · cited 2×
“The SASP reinforces the senescent phenotype in an autocrine fashion and can also stimulate paracrine senescence in bystander cells by participating in a positive feedback loop that activates the transcription of SASP genes (Acosta et al., 2008b, 2013; Coppé et al., 2008).”
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Items 201–205 of 205
Melatonin Preserves Mitochondrial Redox Balance in UVB-Exposed Human Keratinocytes
Okura, M., Takaya, K., Ishii, T., Gagat, M., Wolnicka-Głubisz, A., Kishi, K., Okabe, K., Reiter, R. J., Slominski, A. T., & Kleszczyński, K. (2026) · Antioxidants · doi:10.3390/antiox15080939
Chromatin signaling in aging and cellular senescence
Gagné, L. M., Couteau, F., & Mallette, F. A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-19001-8.00018-0
Liang, J., Cao, H., 任秀敏, Sha, N., Han, X., Jiang, L., Liu, B., & Zhao, W. (2026) · Aging Cell · doi:10.1111/acel.70785
Metadata
- Authors
- Chen, H., Ruiz, P. D., McKimpson, W. M., Novikov, L., Kitsis, R. N., & Gamble, M. J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Gamble, Matthew J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 59
- Issue
- 5
- Pages
- 719-731
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4548812
- OpenAlex
- W1647232018
- Cited by
- 205
- References
- 64
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 24 · 2023: 19 · 2022: 19 · 2021: 30 · 2020: 23 · 2019: 17 · 2018: 23 · 2017: 18 · 2016: 16 · 2015: 1
- FWCI
- 14.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA155232, P30CA013330)
- National Institute of General Medical Sciences (T32GM007491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- macroH2A1, ATM, oncogene-induced senescence, senescence-associated secretory phenotype, paracrine senescence, histone variants, DNA damage response, endoplasmic reticulum stress, reactive oxygen species, positive feedback loop
- MeSH terms
- Cell Line, DNA Damage, Gene Expression Regulation, Histones, Humans, Models, Biological, Oncogenes, Phenotype, Cellular Senescence, Paracrine Communication, Feedback, Physiological, Endoplasmic Reticulum Stress, Ataxia Telangiectasia Mutated Proteins
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