Extrachromosomal DNA: Molecular Perspectives in Aging and Neurodegenerative Diseases

Overview

Journal Intractable Rare Dis Res

Date 2024 Dec 4

PMID 39628626

Authors

Ya-Nan Ma

Ying Xia

Kenji Karako

Peipei Song

Xiqi Hu

Affiliations

Soon will be listed here.

Abstract

Extrachromosomal DNA (ecDNA) refers to a class of circular, non-chromosomal DNA that has recently gained widespread attention due to its potential role in aging and neurodegenerative diseases. The generation of ecDNA is closely associated with processes such as double-strand breaks, micronuclei formation, and the breakage-fusion-bridge (BFB) cycle, all of which are integral to regulation of gene expression, genetic stability, and clonal evolution. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, the aberrant formation of ecDNA is closely linked to defects in DNA repair, alterations in synaptic plasticity, and neuronal dysfunction. The distinct distribution and functional roles of ecDNA in these conditions make it a potential diagnostic biomarker and therapeutic target. This review provides an overview of the mechanisms underlying ecDNA formation and its functions in the nervous system. Additionally, it explores the clinical potential of ecDNA in disease diagnosis, targeted therapy, and personalized medicine, offering new insights for future research and treatment strategies.

References

Goker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y . Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood. 1995; 86(2):677-84. View

Schaser A, Osterberg V, Dent S, Stackhouse T, Wakeham C, Boutros S . Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep. 2019; 9(1):10919. PMC: 6662836. DOI: 10.1038/s41598-019-47227-z. View

Enokido Y, Tamura T, Ito H, Arumughan A, Komuro A, Shiwaku H . Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol. 2010; 189(3):425-43. PMC: 2867301. DOI: 10.1083/jcb.200905138. View

Savelyeva L, Schwab M . Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Lett. 2001; 167(2):115-23. DOI: 10.1016/s0304-3835(01)00472-4. View

Holland A, Cleveland D . Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med. 2012; 18(11):1630-8. PMC: 3616639. DOI: 10.1038/nm.2988. View

Hull R, Houseley J . The adaptive potential of circular DNA accumulation in ageing cells. Curr Genet. 2020; 66(5):889-894. PMC: 7497353. DOI: 10.1007/s00294-020-01069-9. View

Polidori M, Mecocci P, Browne S, Senin U, Beal M . Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex. Neurosci Lett. 1999; 272(1):53-6. DOI: 10.1016/s0304-3940(99)00578-9. View

Sinclair D, Guarente L . Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1998; 91(7):1033-42. DOI: 10.1016/s0092-8674(00)80493-6. View

Jiang X, Zhu D, Okagaki P, Lipsky R, Wu X, Banaudha K . N-methyl-D-aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neurons. Ann N Y Acad Sci. 2003; 993:134-45; discussion 159-60. PMC: 2597300. DOI: 10.1111/j.1749-6632.2003.tb07522.x. View

10.

Wang T, Zhang H, Zhou Y, Shi J . Extrachromosomal circular DNA: a new potential role in cancer progression. J Transl Med. 2021; 19(1):257. PMC: 8194206. DOI: 10.1186/s12967-021-02927-x. View

11.

Von Hoff D, McGill J, Forseth B, Davidson K, Bradley T, Van Devanter D . Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity. Proc Natl Acad Sci U S A. 1992; 89(17):8165-9. PMC: 49877. DOI: 10.1073/pnas.89.17.8165. View

12.

Cohen S, Regev A, Lavi S . Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability. Oncogene. 1997; 14(8):977-85. DOI: 10.1038/sj.onc.1200917. View

13.

Horowitz M, Milanese C, Di Maio R, Hu X, Montero L, Sanders L . Single-cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults. Antioxid Redox Signal. 2011; 15(4):855-71. PMC: 3135271. DOI: 10.1089/ars.2010.3629. View

14.

Storlazzi C, Fioretos T, Surace C, Lonoce A, Mastrorilli A, Strombeck B . MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene. Hum Mol Genet. 2006; 15(6):933-42. DOI: 10.1093/hmg/ddl010. View

15.

Vasquez V, Mitra J, Hegde P, Pandey A, Sengupta S, Mitra S . Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease. J Alzheimers Dis. 2017; 60(s1):S133-S150. PMC: 6172953. DOI: 10.3233/JAD-170342. View

16.

Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau D, Zavala E . NAD supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018; 115(8):E1876-E1885. PMC: 5828618. DOI: 10.1073/pnas.1718819115. View

17.

Oobatake Y, Shimizu N . Double-strand breakage in the extrachromosomal double minutes triggers their aggregation in the nucleus, micronucleation, and morphological transformation. Genes Chromosomes Cancer. 2019; 59(3):133-143. DOI: 10.1002/gcc.22810. View

18.

Madabhushi R, Gao F, Pfenning A, Pan L, Yamakawa S, Seo J . Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell. 2015; 161(7):1592-605. PMC: 4886855. DOI: 10.1016/j.cell.2015.05.032. View

19.

Noer J, Horsdal O, Xiang X, Luo Y, Regenberg B . Extrachromosomal circular DNA in cancer: history, current knowledge, and methods. Trends Genet. 2022; 38(7):766-781. DOI: 10.1016/j.tig.2022.02.007. View

20.

Basenko E, Cesare A, Iyer S, Griffith J, McEachern M . Telomeric circles are abundant in the stn1-M1 mutant that maintains its telomeres through recombination. Nucleic Acids Res. 2009; 38(1):182-9. PMC: 2800209. DOI: 10.1093/nar/gkp814. View