Illegitimate and Repeated Genomic Integration of Cell-Free Chromatin in the Aetiology of Somatic Mosaicism, Ageing, Chronic Diseases and Cancer.
DNA damage
NFκB
apoptosis
cell death
chromosomal damage
chromosomal mosaicism
chromosomes
circulating nucleic acids
inflammation
Journal
Genes
ISSN: 2073-4425
Titre abrégé: Genes (Basel)
Pays: Switzerland
ID NLM: 101551097
Informations de publication
Date de publication:
28 05 2019
28 05 2019
Historique:
received:
15
04
2019
revised:
15
05
2019
accepted:
22
05
2019
entrez:
31
5
2019
pubmed:
31
5
2019
medline:
31
5
2019
Statut:
epublish
Résumé
Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal variations and footprints of transposable elements. High-throughput sequencing has led to increasing detection of mosaicism in healthy individuals which is related to ageing, neuro-degenerative disorders, diabetes mellitus, cardiovascular diseases and cancer. These age-related disorders are also known to be associated with significant increase in DNA damage and inflammation. Herein, we discuss a newly described phenomenon wherein the genome is under constant assault by illegitimate integration of cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body every day. We propose that such repeated genomic integration of cfCh followed by dsDNA breaks and repair by non-homologous-end-joining as well as physical damage to chromosomes occurring throughout life may lead to somatic/chromosomal mosaicism which would increase with age. We also discuss the recent finding that genomic integration of cfCh and the accompanying DNA damage is associated with marked activation of inflammatory cytokines. Thus, the triple pathologies of somatic mosaicism, DNA/chromosomal damage and inflammation brought about by a common mechanism of genomic integration of cfCh may help to provide an unifying model for the understanding of aetiologies of the inter-related conditions of ageing, degenerative disorders and cancer.
Identifiants
pubmed: 31142004
pii: genes10060407
doi: 10.3390/genes10060407
pmc: PMC6628102
pii:
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Science. 2018 Nov 23;362(6417):911-917
pubmed: 30337457
Hum Genet. 2017 May;136(5):657-663
pubmed: 28424864
Cell Death Discov. 2017 May 29;3:17015
pubmed: 28580170
Mutat Res. 2004 Oct 4;554(1-2):297-304
pubmed: 15450427
J Carcinog. 2006 May 11;5:14
pubmed: 16689993
Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000067
pubmed: 20066093
Biomaterials. 2013 Sep;34(27):6328-38
pubmed: 23746856
Nat Genet. 2012 May 06;44(6):642-50
pubmed: 22561516
Cell Rep. 2014 Sep 11;8(5):1280-9
pubmed: 25159146
Cytogenet Genome Res. 2007;118(2-4):237-46
pubmed: 18000376
Mutat Res. 2016 Nov - Dec;793-794:15-21
pubmed: 27768916
N Engl J Med. 2014 Dec 25;371(26):2477-87
pubmed: 25426838
Hum Mol Genet. 2010 Apr 1;19(7):1263-75
pubmed: 20053666
Annu Rev Genet. 2018 Nov 23;52:397-419
pubmed: 30212236
Clin Exp Immunol. 1999 Aug;117(2):403-11
pubmed: 10444277
J Biosci. 2015 Mar;40(1):91-111
pubmed: 25740145
Sci Signal. 2011 Jan 18;4(156):pe2
pubmed: 21245467
Nat Commun. 2014 Jun 27;5:4227
pubmed: 24970340
Mech Ageing Dev. 2011 Jan-Feb;132(1-2):20-6
pubmed: 21078336
Cell Death Dis. 2018 Nov 15;9(12):1142
pubmed: 30442925
Mutat Res. 2018 Mar;808:48-52
pubmed: 29518635
J Natl Cancer Inst. 1970 Oct;45(4):773-82
pubmed: 5513503
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4612-E4620
pubmed: 28533362
Cytogenet Cell Genet. 1997;76(1-2):53-7
pubmed: 9154128
PLoS One. 2007 Jun 27;2(6):e558
pubmed: 17593959
Nat Rev Cardiol. 2018 Sep;15(9):505-522
pubmed: 30065258
Am J Hum Genet. 1983 Jan;35(1):110-6
pubmed: 6218752
Trends Genet. 2018 Jul;34(7):545-557
pubmed: 29731376
Cell. 2015 Apr 9;161(2):228-39
pubmed: 25860606
Am J Hum Genet. 2016 Jun 2;98(6):1208-1219
pubmed: 27231129
PLoS One. 2015 Feb 17;10(2):e0117854
pubmed: 25689626
Mol Genet Genomics. 2016 Apr;291(2):513-30
pubmed: 26481646
Cancer Biother Radiopharm. 2002 Aug;17(4):405-26
pubmed: 12396705
Cancer Lett. 2004 Sep 30;213(2):203-12
pubmed: 15327836
J Immunol. 2005 Jul 1;175(1):575-8
pubmed: 15972694
Science. 2015 May 22;348(6237):880-6
pubmed: 25999502
Oncogene. 1999 Nov 22;18(49):6853-66
pubmed: 10602461
Cytogenet Genome Res. 2007;116(3):181-5
pubmed: 17317957
Curr Genomics. 2010 Sep;11(6):426-31
pubmed: 21358987
Genes Dev. 2017 Feb 15;31(4):353-369
pubmed: 28279982
Clin Chem. 2005 Aug;51(8):1544-6
pubmed: 16040855
Immunity. 2015 Feb 17;42(2):332-343
pubmed: 25692705
Nucleic Acids Res. 2016 Mar 18;44(5):2075-84
pubmed: 26883632
Ann N Y Acad Sci. 2008 Aug;1137:180-9
pubmed: 18837945
Am J Hum Genet. 2012 Feb 10;90(2):217-28
pubmed: 22305530
Science. 2003 Nov 28;302(5650):1516-7
pubmed: 14645835
Exp Gerontol. 2015 Feb;62:45-52
pubmed: 25576678
Nat Genet. 2015 Apr;47(4):367-372
pubmed: 25730763
Science. 2013 Nov 1;342(6158):632-7
pubmed: 24179226
Int J Radiat Oncol Biol Phys. 1995 Nov 1;33(4):781-96
pubmed: 7591884
Cancer Res. 2004 Dec 1;64(23):8550-7
pubmed: 15574761
Nat Rev Immunol. 2015 Dec;15(12):760-70
pubmed: 26603901
Clin Chim Acta. 2008 Jan;387(1-2):55-8
pubmed: 17916343
J Clin Invest. 1990 Jul;86(1):69-74
pubmed: 2365827
Mol Cell. 2014 Sep 18;55(6):829-842
pubmed: 25201414
F1000Res. 2015 Sep 30;4:924
pubmed: 26664710
Ann N Y Acad Sci. 2006 Sep;1075:191-6
pubmed: 17108211
J Immunol. 1996 Feb 1;156(3):1151-6
pubmed: 8557992
Mol Cytogenet. 2008 Nov 25;1:26
pubmed: 19032785
Ann Rheum Dis. 2003 Jan;62(1):10-4
pubmed: 12480662
Ann N Y Acad Sci. 2008 Aug;1137:218-21
pubmed: 18837950
Genome Med. 2018 Mar 20;10(1):21
pubmed: 29558971
J Med Genet. 2007 Aug;44(8):521-5
pubmed: 17483303
Mol Cell. 2004 Jun 4;14(5):611-23
pubmed: 15175156
Nat Rev Genet. 2017 Feb;18(2):128-142
pubmed: 27941868
Nature. 2008 Jul 24;454(7203):436-44
pubmed: 18650914
Genome Res. 2017 Oct;27(10):1704-1714
pubmed: 28855261
Nat Cell Biol. 2017 Sep;19(9):1061-1070
pubmed: 28759028
Genes Chromosomes Cancer. 1992 Jul;5(1):83-8
pubmed: 1384666
Neurol Neurochir Pol. 2003 Mar-Apr;37(2):315-26
pubmed: 14558480
Nat Genet. 2014 Jun;46(6):624-8
pubmed: 24777449
Nature. 1980 Apr 10;284(5756):555-6
pubmed: 6245367
Genes Dev. 2004 Jan 1;18(1):1-11
pubmed: 14724175
Mol Cell. 2015 Nov 19;60(4):547-60
pubmed: 26590714
Nat Rev Immunol. 2011 Feb;11(2):98-107
pubmed: 21233852
Cell. 2007 Dec 28;131(7):1235-47
pubmed: 18160035
Nat Genet. 2013 Sep;45(9):1040-3
pubmed: 23852171
Neural Plast. 2018 Jun 28;2018:2406170
pubmed: 30050570
Br J Cancer. 1972 Aug;26(4):239-57
pubmed: 4561027
Pancreas. 1998 Jul;17(1):89-97
pubmed: 9667526
J Biosci. 2012 Jun;37(2):301-12
pubmed: 22581336
Curr Alzheimer Res. 2009 Feb;6(1):36-47
pubmed: 19199873
J Histochem Cytochem. 2005 Mar;53(3):375-80
pubmed: 15750024
Nature. 1998 Jan 1;391(6662):96-9
pubmed: 9422513
Genome Res. 2017 Apr;27(4):512-523
pubmed: 28235832
Nat Genet. 2012 May 06;44(6):651-8
pubmed: 22561519
Clin Chem. 2007 Dec;53(12):2215
pubmed: 18267930
Science. 2017 Apr 28;356(6336):
pubmed: 28450582
EMBO J. 2003 May 1;22(9):2274-83
pubmed: 12727893
Clin Chem Lab Med. 2001 Jul;39(7):596-605
pubmed: 11522104
Elife. 2016 Feb 22;5:
pubmed: 26901440
Cell Div. 2015 May 20;10:3
pubmed: 26015801
Circ J. 2014;78(1):42-50
pubmed: 24334614
Genome Res. 2008 Jul;18(7):1011-9
pubmed: 18593815
Schizophr Res. 2008 Jan;98(1-3):139-47
pubmed: 17889509
Annu Rev Genet. 2014;48:1-27
pubmed: 25036377
Prog Nucleic Acid Res Mol Biol. 1971;11:103-92
pubmed: 4934248
N Engl J Med. 2014 Dec 25;371(26):2488-98
pubmed: 25426837
EMBO J. 2002 May 1;21(9):2207-19
pubmed: 11980718
F1000Res. 2015 Oct 27;4:1145
pubmed: 27134724
Nature. 2006 Oct 26;443(7114):998-1002
pubmed: 17066036
Hum Genet. 1996 Oct;98(4):409-14
pubmed: 8792813
FASEB J. 2008 Jul;22(7):2232-42
pubmed: 18356302
J Neurosci. 2007 Jun 27;27(26):6859-67
pubmed: 17596434
Cell Death Differ. 2008 Feb;15(2):243-50
pubmed: 17571081
Cancer Metastasis Rev. 2016 Sep;35(3):347-76
pubmed: 27392603
Trends Endocrinol Metab. 2017 Mar;28(3):199-212
pubmed: 27789101
Science. 2015 Oct 2;350(6256):94-98
pubmed: 26430121
Nature. 2017 Oct 19;550(7676):402-406
pubmed: 28976970
Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006346
pubmed: 22315714
Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10804-10809
pubmed: 30262650
Nature. 2018 Nov;563(7733):639-645
pubmed: 30464338