{"id":29000,"date":"2023-09-13T20:00:00","date_gmt":"2023-09-14T00:00:00","guid":{"rendered":"https:\/\/platohealth.ai\/foxo-transcription-factors-as-mediators-of-stress-adaptation-nature-reviews-molecular-cell-biology\/"},"modified":"2023-09-16T12:20:05","modified_gmt":"2023-09-16T16:20:05","slug":"foxo-transcription-factors-as-mediators-of-stress-adaptation-nature-reviews-molecular-cell-biology","status":"publish","type":"post","link":"https:\/\/platohealth.ai\/foxo-transcription-factors-as-mediators-of-stress-adaptation-nature-reviews-molecular-cell-biology\/","title":{"rendered":"FOXO transcription factors as mediators of stress adaptation – Nature Reviews Molecular Cell Biology","gt_translate_keys":[{"key":"rendered","format":"text"}]},"content":{"rendered":"
Gems, D. et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans<\/i>. Genetics<\/i> 150<\/b>, 129\u2013155 (1998).<\/p>\n
Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans<\/i>. Nature<\/i> 424<\/b>, 277\u2013283 (2003).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans<\/i> life-span and metabolism. Science<\/i> 300<\/b>, 644\u2013647 (2003).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Jenkins, N. L., McColl, G. & Lithgow, G. J. Fitness cost of extended lifespan in Caenorhabditis elegans<\/i>. Proc. Biol. Sci.<\/i> 271<\/b>, 2523\u20132526 (2004).<\/p>\n Article<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell<\/i> 120<\/b>, 449\u2013460 (2005). This is one of the first papers to show that a single specific genetic mutation (<\/b>daf-2<\/i><\/b>) can increase lifespan and can be reverted by a second mutation (<\/b>daf-16<\/i><\/b>), revealing a connection between insulin signalling and lifespan<\/b>.<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A. C. elegans<\/i> mutant that lives twice as long as wild type. Nature<\/i> 366<\/b>, 461\u2013464 (1993).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA<\/i> 105<\/b>, 13987\u201313992 (2008).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Santo, E. E. et al. FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity. Aging Cell<\/i> 22<\/b>, e13763 (2023).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Eijkelenboom, A. & Burgering, B. M. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol.<\/i> 14<\/b>, 83\u201397 (2013).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Liang, R. & Ghaffari, S. Stem cells seen through the FOXO lens: an evolving paradigm. Curr. Top. Dev. Biol.<\/i> 127<\/b>, 23\u201347 (2018).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance physiologic oxid. stress. Cell<\/i> 128<\/b>, 325\u2013339 (2007). This study shows the redundancy of FOXO1, FOXO3 and FOXO4 in HSC maintenance and that antioxidant defence downstream of FOXO is a key driver of stem cell maintenance.<\/b><\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Shimokawa, I. et al. The life-extending effect of dietary restriction requires Foxo3 in mice. Aging Cell<\/i> 14<\/b>, 707\u2013709 (2015).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hwang, I. et al. FOXO protects against age-progressive axonal degeneration. Aging Cell<\/i> 17<\/b>, e12701 (2018).<\/p>\n Article<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Du, S. et al. FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology. Aging Cell<\/i> 20<\/b>, e13432 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hedrick, S. M., Hess Michelini, R., Doedens, A. L., Goldrath, A. W. & Stone, E. L. FOXO transcription factors throughout T cell biology. Nat. Rev. Immunol.<\/i> 12<\/b>, 649\u2013661 (2012).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Calissi, G., Lam, E. W. & Link, W. Therapeutic strategies targeting FOXO transcription factors. Nat. Rev. Drug Discov.<\/i> 20<\/b>, 21\u201338 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Brown, A. K. & Webb, A. E. Regulation of FOXO factors in mammalian cells. Curr. Top. Dev. Biol.<\/i> 127<\/b>, 165\u2013192 (2018).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Calnan, D. R. & Brunet, A. The FoxO code. Oncogene<\/i> 27<\/b>, 2276\u20132288 (2008).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Franz, F. et al. The transcriptional regulation of FOXO genes in thyrocytes. Horm. Metab. Res.<\/i> 48<\/b>, 601\u2013606 (2016).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Urbanek, P. & Klotz, L. O. Posttranscriptional regulation of FOXO expression: microRNAs and beyond. Br. J. Pharmacol.<\/i> 174<\/b>, 1514\u20131532 (2017).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Asmamaw, M. D., Liu, Y., Zheng, Y. C., Shi, X. J. & Liu, H. M. Skp2 in the ubiquitin\u2013proteasome system: a comprehensive review. Med. Res. Rev.<\/i> 40<\/b>, 1920\u20131949 (2020).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Brenkman, A. B., de Keizer, P. L., van den Broek, N. J., Jochemsen, A. G. & Burgering, B. M. Mdm2 induces mono-ubiquitination of FOXO4. PLoS ONE<\/i> 3<\/b>, e2819 (2008).<\/p>\n Article<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Huang, H. & Tindall, D. J. Regulation of FOXO protein stability via ubiquitination and proteasome degradation. Biochim. Biophys. Acta<\/i> 1813<\/b>, 1961\u20131964 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Wang, X., Wang, J. & Jiang, X. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J. Biol. Chem.<\/i> 286<\/b>, 23725\u201323734 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Grossman, S. R. et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science<\/i> 300<\/b>, 342\u2013344 (2003).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Zhou, B. P. et al. HER-2\/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat. Cell Biol.<\/i> 3<\/b>, 973\u2013982 (2001).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase\/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA<\/i> 98<\/b>, 11598\u201311603 (2001).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n van der Horst, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7\/HAUSP. Nat. Cell Biol.<\/i> 8<\/b>, 1064\u20131073 (2006).<\/p>\n Article<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Heimbucher, T. & Hunter, T. The C. elegans<\/i> ortholog of USP7 controls DAF-16 stability in insulin\/IGF-1-like signaling. Worm<\/i> 4<\/b>, e1103429 (2015).<\/p>\n Article<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Kops, G. J. et al. Direct control of the forkhead transcription factor AFX by protein kinase B. Nature<\/i> 398<\/b>, 630\u2013634 (1999).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell<\/i> 96<\/b>, 857\u2013868 (1999). This study and the study by Kops et al. (1999) are the first to show that the regulation of FOXOs, the orthologues of DAF-16 in mammalians, are directly controlled by AKT and PI3K signalling, thereby showing evolutionary conservation.<\/b><\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Brownawell, A. M., Kops, G. J., Macara, I. G. & Burgering, B. M. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol. Cell Biol.<\/i> 21<\/b>, 3534\u20133546 (2001).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Essers, M. A. et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J.<\/i> 23<\/b>, 4802\u20134812 (2004).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Putker, M. et al. Redox-dependent control of FOXO\/DAF-16 by transportin-1. Mol. Cell<\/i> 49<\/b>, 730\u2013742 (2013).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Putker, M. et al. Evolutionary acquisition of cysteines determines FOXO paralog-specific redox signaling. Antioxid. Redox Signal.<\/i> 22<\/b>, 15\u201328 (2015).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev.<\/i> 25<\/b>, 2227\u20132241 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Clark, K. L., Halay, E. D., Lai, E. & Burley, S. K. Co-crystal structure of the HNF-3\/fork head DNA-recognition motif resembles histone H5. Nature<\/i> 364<\/b>, 412\u2013420 (1993).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Wang, F. et al. Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J. Mol. Biol.<\/i> 384<\/b>, 590\u2013603 (2008).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Bourgeois, B. et al. Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function. Cell Rep.<\/i> 36<\/b>, 109446 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Obsil, T. & Obsilova, V. Structural basis for DNA recognition by FOXO proteins. Biochim. Biophys. Acta<\/i> 1813<\/b>, 1946\u20131953 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Li, J. et al. Mechanism of forkhead transcription factors binding to a novel palindromic DNA site. Nucleic Acids Res.<\/i> 49<\/b>, 3573\u20133583 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Psenakova, K. et al. Forkhead domains of FOXO transcription factors differ in both overall conformation and dynamics. Cells<\/i> 8<\/b>, 966 (2019).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Sugase, K., Dyson, H. J. & Wright, P. E. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature<\/i> 447<\/b>, 1021\u20131025 (2007).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Shoemaker, B. A., Portman, J. J. & Wolynes, P. G. Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc. Natl Acad. Sci. USA<\/i> 97<\/b>, 8868\u20138873 (2000).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Dansen, T. B. et al. Redox-sensitive cysteines bridge p300\/CBP-mediated acetylation and FoxO4 activity. Nat. Chem. Biol.<\/i> 5<\/b>, 664\u2013672 (2009). This study is among the first to show that redox signalling, similar to growth factor signalling, proceeds through protein\u2013<\/b>protein interactions that are enforced by redox-sensitive cysteine disulfide bridges.<\/b><\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Sies, H. & Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol.<\/i> 21<\/b>, 363\u2013383 (2020).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n van der Horst, A. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2. J. Biol. Chem.<\/i> 279<\/b>, 28873\u201328879 (2004).<\/p>\n Article<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Yoshimochi, K., Daitoku, H. & Fukamizu, A. PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner. J. Recept. Signal Transduct. Res.<\/i> 30<\/b>, 43\u201349 (2010).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Adamowicz, M., Vermezovic, J. & d\u2019Adda di Fagagna, F. NOTCH1 inhibits activation of ATM by impairing the formation of an ATM-FOXO3a-KAT5\/Tip60 complex. Cell Rep.<\/i> 16<\/b>, 2068\u20132076 (2016).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science<\/i> 303<\/b>, 2011\u20132015 (2004). This study, together with van der Horst et al. (2004) provides a mechanistic link between FOXO and SIRT, which were independently shown to affect lifespan.<\/b><\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Daitoku, H. et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl Acad. Sci. USA<\/i> 101<\/b>, 10042\u201310047 (2004).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Tseng, A. H., Wu, L. H., Shieh, S. S. & Wang, D. L. SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia. Biochem. J.<\/i> 464<\/b>, 157\u2013168 (2014).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell<\/i> 145<\/b>, 607\u2013621 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Daitoku, H., Sakamaki, J. & Fukamizu, A. Regulation of FoxO transcription factors by acetylation and protein\u2013protein interactions. Biochim. Biophys. Acta<\/i> 1813<\/b>, 1954\u20131960 (2011).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Riedel, C. G. et al. DAF-16 employs the chromatin remodeller SWI\/SNF to promote stress resistance and longevity. Nat. Cell Biol.<\/i> 15<\/b>, 491\u2013501 (2013).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Webb, A. E. & Brunet, A. FOXO flips the longevity SWItch. Nat. Cell Biol.<\/i> 15<\/b>, 444\u2013446 (2013).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Mattila, J., Kallijarvi, J. & Puig, O. RNAi screening for kinases and phosphatases identifies FoxO regulators. Proc. Natl Acad. Sci. USA<\/i> 105<\/b>, 14873\u201314878 (2008).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Liu, J. et al. Targeting the BRD4\/FOXO3a\/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nat. Commun.<\/i> 9<\/b>, 5200 (2018).<\/p>\n Article<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Webb, A. E., Kundaje, A. & Brunet, A. Characterization of the direct targets of FOXO transcription factors throughout evolution. Aging Cell<\/i> 15<\/b>, 673\u2013685 (2016).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hao, N. & O\u2019Shea, E. K. Signal-dependent dynamics of transcription factor translocation controls gene expression. Nat. Struct. Mol. Biol.<\/i> 19<\/b>, 31\u201339 (2011).<\/p>\n Article<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Demirbas, B. et al. Control of C. elegans<\/i> growth arrest by stochastic, yet synchronized DAF-16\/FOXO nuclear translocation pulses. Preprint at bioRxiv<\/i> https:\/\/doi.org\/10.1101\/2023.07.05.547674<\/a> (2023).<\/p>\n<\/li>\n Lasick, K. A. et al. FOXO nuclear shuttling dynamics are stimulus-dependent and correspond with cell fate. Mol. Biol. Cell<\/i> 34<\/b>, ar21 (2023).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone: DNA contacts by FoxO1. J. Biol. Chem.<\/i> 282<\/b>, 35583\u201335593 (2007).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hatta, M., Liu, F. & Cirillo, L. A. Acetylation curtails nucleosome binding, not stable nucleosome remodeling, by FoxO1. Biochem. Biophys. Res. Commun.<\/i> 379<\/b>, 1005\u20131008 (2009).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Eijkelenboom, A., Mokry, M., Smits, L. M., Nieuwenhuis, E. E. & Burgering, B. M. FOXO3 selectively amplifies enhancer activity to establish target gene regulation. Cell Rep.<\/i> 5<\/b>, 1664\u20131678 (2013).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Newman, J. R. et al. Single-cell proteomic analysis of S. cerevisiae<\/i> reveals the architecture of biological noise. Nature<\/i> 441<\/b>, 840\u2013846 (2006).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Allgayer, J., Kitsera, N., Bartelt, S., Epe, B. & Khobta, A. Widespread transcriptional gene inactivation initiated by a repair intermediate of 8-oxoguanine. Nucleic Acids Res.<\/i> 44<\/b>, 7267\u20137280 (2016).<\/p>\n CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Desai, R. V. et al. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Science<\/i> 373<\/b>, eabc6506 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Raser, J. M. & O\u2019Shea, E. K. Noise in gene expression: origins, consequences, and control. Science<\/i> 309<\/b>, 2010\u20132013 (2005).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Munsky, B., Neuert, G. & van Oudenaarden, A. Using gene expression noise to understand gene regulation. Science<\/i> 336<\/b>, 183\u2013187 (2012).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Wong, V. C. et al. NF-kappaB-chromatin interactions drive diverse phenotypes by modulating transcriptional noise. Cell Rep.<\/i> 22<\/b>, 585\u2013599 (2018).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Comandante-Lou, N., Baumann, D. G. & Fallahi-Sichani, M. AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells. Cell Rep.<\/i> 40<\/b>, 111147 (2022).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Bahar, R. et al. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature<\/i> 441<\/b>, 1011\u20131014 (2006).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Somel, M., Khaitovich, P., Bahn, S., Paabo, S. & Lachmann, M. Gene expression becomes heterogeneous with age. Curr. Biol.<\/i> 16<\/b>, R359\u2013R360 (2006).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Rangaraju, S. et al. Suppression of transcriptional drift extends C. elegans<\/i> lifespan by postponing the onset of mortality. eL<\/i>ife<\/i> 4<\/b>, e08833 (2015).<\/p>\n Google Scholar<\/a> <\/p>\n<\/li>\n Cheung, P. et al. Single-cell chromatin modification profiling reveals increased epigenetic variations with aging. Cell<\/i> 173<\/b>, 1385\u20131397.e14 (2018).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Burgess, D. J. Human epigenetics: showing your age. Nat. Rev. Genet.<\/i> 14<\/b>, 6 (2013).<\/p>\n Article<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Booth, L. N. & Brunet, A. The aging epigenome. Mol. Cell<\/i> 62<\/b>, 728\u2013744 (2016).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Fielenbach, N. & Antebi, A. C. elegans<\/i> Dauer formation and the molecular basis of plasticity. Genes Dev.<\/i> 22<\/b>, 2149\u20132165 (2008).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature<\/i> 404<\/b>, 782\u2013787 (2000). This study links FOXO function to inhibition of the cell cycle, thereby suggesting a role for FOXOs in tissue homeostasis and cancer.<\/b><\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Furukawa-Hibi, Y., Yoshida-Araki, K., Ohta, T., Ikeda, K. & Motoyama, N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J. Biol. Chem.<\/i> 277<\/b>, 26729\u201326732 (2002).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Hornsveld, M. et al. A FOXO-dependent replication checkpoint restricts proliferation of damaged cells. Cell Rep.<\/i> 34<\/b>, 108675 (2021).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Sekimoto, T., Fukumoto, M. & Yoneda, Y. 14-3-3 Suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1). EMBO J.<\/i> 23<\/b>, 1934\u20131942 (2004).<\/p>\n Article<\/a> CAS<\/a> PubMed<\/a> PubMed Central<\/a> Google Scholar<\/a> <\/p>\n<\/li>\n Blain, S. W. & Massague, J. Breast cancer banishes p27 from nucleus. Nat. Med.<\/i>