ArticleNature communications2025
p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28citing papers in PubMed
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Who cites it
28 citing papers in PubMed.
- Review
- Immune-epigenetic convergence in biomaterial-guided tissue regeneration.Materials today. Bio · 2026Article
- Cellular senescence and regulated cell death in cancer: mechanisms, cross-regulatory networks and therapeutic implications.Journal of hematology & oncology · 2026Review
- Transcriptomic evidence of remodeling in postpartum levator ani muscle associated with maternal age and recovery time after first vaginal delivery.American journal of obstetrics and gynecology · 2026Article
- Disruption of CDK4/6-RARα-NF-κB axis attenuates senescence-associated inflammation and improves function during aging and following chemotherapy.Nature aging · 2026Article
- Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.Nature aging · 2026Article
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- Genomic, epigenomic and transcriptomic regulation of cellular senescence.Nature reviews. Genetics · 2026Review
- Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.Nature aging · 2026Article
- Dysregulation of the DNA repair‑immune axis: Targeted therapeutic strategies for autoimmune diseases (Review).International journal of molecular medicine · 2026Review
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- Cellular senescence dysregulates antiviral interferon responses in idiopathic pulmonary fibrosis.bioRxiv : the preprint server for biology · 2026Article
- DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons.bioRxiv : the preprint server for biology · 2026Article
- Association of radiotherapy with atrial fibrillation-related gene expression in breast cancer patients: a study based on the TCGA-BRCA database.Discover oncology · 2026Article
- Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage.Aging cell · 2026Article
- Senescent cells secrete chromatin components via senescence-associated extracellular particles.Research square · 2026Article
- SMP30: a promising cancer biomarker with therapeutic potential.Open medicine (Warsaw, Poland) · 2026Review
- Senescent cells secrete chromatin components via senescence-associated extracellular particles.bioRxiv : the preprint server for biology · 2025Article
- Elimination of docetaxel-induced senescence attenuates malignant progression in RB1-deficient CRPC.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Nanocomposite-loaded hybrid microneedles reshape dermal microenvironment through senolytic delivery and collagen XVII-mediated barrier repair.Materials today. Bio · 2025Article
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Authors and funding
34 authors.
Karl N MillerCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA. kmiller@sbpdiscovery.org.
Brightany LiCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Hannah R Pierce-HoffmanCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Shreeya PatelCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Xue LeiCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Adarsh RajeshCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Marcos G TenecheCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0003-4785-7987
Aaron P HavasCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0003-4291-8015
Armin GandhiCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-8246-4663
Carolina Cano MacipCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Jun LyuLaboratory of Biochemistry and Molecular Biology; National Cancer Institute; National Institutes of Health, Bethesda, MD, USA.
Stella G VictorelliDepartment of Physiology and Biomedical Engineering; Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0001-5573-8019
Seung-Hwa WooDepartment of Physiology and Biomedical Engineering; Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-9336-4457
Anthony B LagnadoDepartment of Physiology and Biomedical Engineering; Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-9380-5179
Michael A LaPortaNOMIS Center for Immunobiology and Microbial Pathogenesis; Salk Institute for Biological Studies, La Jolla, CA, USA.ORCID http://orcid.org/0009-0001-0461-5614
Tianhui LiuCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Nirmalya DasguptaCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Sha LiCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-1006-1785
Andrew DavisCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Anatoly KorotkovDepartments of Biology and Medicine; University of Rochester, Rochester, NY, USA.
Erik HulteniusCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Zichen GaoCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Yoav AltmanShared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0001-6075-1111
Rebecca A PorrittShared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-0973-5092
Guillermina GarciaShared Resources; NCI-designated Cancer Center; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Carolin MoglerInstitute of Pathology; School of Medicine and Health; Technical University Munich (TUM), Munich, Germany.ORCID http://orcid.org/0000-0003-3400-7254
Andrei SeluanovDepartments of Biology and Medicine; University of Rochester, Rochester, NY, USA.
Vera GorbunovaDepartments of Biology and Medicine; University of Rochester, Rochester, NY, USA.ORCID http://orcid.org/0000-0001-8979-0333
Susan M KaechNOMIS Center for Immunobiology and Microbial Pathogenesis; Salk Institute for Biological Studies, La Jolla, CA, USA.ORCID http://orcid.org/0000-0003-1674-1420
Xiao TianCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA.
Zhixun DouCenter for Regenerative Medicine, Department of Medicine; Massachusetts General Research Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3069-3907
Chongyi ChenLaboratory of Biochemistry and Molecular Biology; National Cancer Institute; National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-0504-5369
João F PassosDepartment of Physiology and Biomedical Engineering; Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0001-8765-1890
Peter D AdamsCancer Genome and Epigenetics Program; Sanford Burnham Prebys MDI, La Jolla, CA, USA. padams@sbpdiscovery.org.ORCID http://orcid.org/0000-0002-0684-1770
Funding
Tumor Microenvironment and Cancer ImmunologyP30CA030199 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI ELENA B PASQUALE · 1985 to 2026
$107.2MThe role of hyaluronan in longevity and cancer resistance of longest-lived rodentP01AG047200 · NIA · UNIVERSITY OF ROCHESTER · PI Vadim N. Gladyshev · 2014 to 2026
$36.9MSomatic Activation of Retrotransposition: A New Molecular Mechanism of Aging?P01AG051449 · NIA · BROWN UNIVERSITY · PI John M Sedivy · 2016 to 2026
$30.4MSTRUCTURAL BASIS FOR EPIGENETICS IN AGING AND LONGEVITYP01AG031862 · NIA · WISTAR INSTITUTE · PI BERGER, SHELLEY L · 2008 to 2022
$28.3MThe dynamics of chromatin topology in human cellsZIABC011884 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI CHEN, CHONGYI · 2019 to 2025
$9.2MThe role of SIRT6 posttranslational modifications in aging and genome stability. Supplement: Testing SIRT6 activators as potential Alzheimer's disease therapy.R01AG027237 · NIA · UNIVERSITY OF ROCHESTER · PI Vera Gorbunova · 2006 to 2026
$6.2MRegulation of epigenome stability by SIRT6 during aging. Supplement: Does centenarian variant of SIRT6 or bowhead whale SIRT6 confer protection from Alzheimer's disease?R37AG046320 · NIA · UNIVERSITY OF ROCHESTER · PI Andrei Seluanov · 2019 to 2026
$4.7MCytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventionsR01AG071861 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI ADAMS, PETER D. · 2021 to 2025
$2.3MNucleus-to-cytoplasm trafficking of chromatin fragments in senescence and agingR01AG082785 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI Zhixun Dou · 2023 to 2026
$2.2MThe role of sub-lethal mitochondrial apoptotic stress in cellular senescenceR01AG068048 · NIA · MAYO CLINIC ROCHESTER · PI PASSOS, JOAO · 2020 to 2024
$2.2MRegulation of genome stability by SITR6R01AG046320 · NIA · UNIVERSITY OF ROCHESTER · PI SELUANOV, ANDREI · 2014 to 2018
$1.9MDevelopment of machine learning software to quantitatively map telomere induced senescence in tissue sections during agingUH3CA268103 · NCI · MAYO CLINIC ROCHESTER · PI PASSOS, JOAO · 2023 to 2025
$1.6MAmerican Federation for Aging Research (American Federation for Aging Research, Inc.) Reboot FundGlenn Foundation for Medical Research PD19131Intramural NIH HHS ZIA BC011884NCI NIH HHS P30 CA030199NCI NIH HHS UG3 CA268103NCI NIH HHS UH3 CA268103NIA NIH HHS F32 AG066459NIA NIH HHS K99 AG073450NIA NIH HHS P01 AG031862NIA NIH HHS P01 AG047200NIA NIH HHS P01 AG051449NIA NIH HHS R00 AG068303NIA NIH HHS R01 AG027237NIA NIH HHS R01 AG046320NIA NIH HHS R01 AG068048NIA NIH HHS R01 AG071861NIA NIH HHS R01 AG082708NIA NIH HHS R01 AG082785NIA NIH HHS R37 AG046320U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 1ZIABC011884U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30CA03199U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) UG3CA268103U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) F32AG066459U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) K99AG073450U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) P01AG031862U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) P01AG047200U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG027237U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG071861U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG082785U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG68048U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG82708
Abstract
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
Indexed as
Cellular SenescenceChromatinDNA RepairInflammationTumor Suppressor Protein p53AgingAnimalsAtaxia Telangiectasia Mutated ProteinsCytoplasmDNA DamageGenomic InstabilityHistonesHumansMacrophagesMaleMiceAtaxia Telangiectasia Mutated ProteinsChromatingamma-H2AX protein, mouseHistonesMdm2 protein, mouseProto-Oncogene Proteins c-mdm2Tumor Suppressor Protein p53
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