Splicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteins.
Adaptor Proteins, Signal Transducing
/ genetics
Alternative Splicing
/ genetics
Carcinogenesis
/ genetics
Cell Cycle Proteins
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Gene Knockdown Techniques
Genome, Human
/ genetics
Genomic Instability
/ genetics
Hep G2 Cells
Humans
Liver Neoplasms
/ genetics
RNA Splicing
/ genetics
RNA Splicing Factors
/ genetics
Serine-Arginine Splicing Factors
/ genetics
Sister Chromatid Exchange
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
23 04 2019
23 04 2019
Historique:
accepted:
08
01
2019
revised:
21
11
2018
received:
26
07
2018
pubmed:
19
1
2019
medline:
11
10
2019
entrez:
19
1
2019
Statut:
ppublish
Résumé
Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
Identifiants
pubmed: 30657957
pii: 5290488
doi: 10.1093/nar/gkz014
pmc: PMC6468163
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CDCA5 protein, human
0
Cell Cycle Proteins
0
RNA Splicing Factors
0
SLU7 protein, human
0
SRSF1 protein, human
0
SRSF3 protein, human
0
Serine-Arginine Splicing Factors
170974-22-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3450-3466Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Cell Rep. 2018 Feb 20;22(8):1994-2005
pubmed: 29466728
Mol Cell. 2009 Jul 31;35(2):228-39
pubmed: 19647519
Mol Cell Biol. 1997 Jun;17(6):3116-24
pubmed: 9154810
J Clin Invest. 2015 Mar 2;125(3):981-92
pubmed: 25621497
Cancer Cell. 2017 Sep 11;32(3):342-359.e10
pubmed: 28898696
Cell Cycle. 2014;13(10):1524-9
pubmed: 24694687
Annu Rev Biochem. 2016 Jun 2;85:291-317
pubmed: 27023844
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2207-12
pubmed: 20133864
Cell Cycle. 2015;14(12):1873-83
pubmed: 25892155
Genome Biol. 2012;13(3):R17
pubmed: 22436691
EMBO Rep. 2014 Sep;15(9):956-64
pubmed: 25092792
Curr Opin Cell Biol. 2001 Dec;13(6):754-61
pubmed: 11698193
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Science. 2013 May 3;340(6132):619-21
pubmed: 23641115
Genome Biol. 2015 Sep 21;16:201
pubmed: 26392272
Adv Clin Chem. 2015;69:91-138
pubmed: 25934360
Gastroenterology. 2009 Nov;137(5):1805-15.e1-4
pubmed: 19664633
Mol Cell. 2017 Mar 2;65(5):832-847.e4
pubmed: 28257700
Mol Cancer Res. 2012 Sep;10(9):1216-27
pubmed: 22859706
Mol Cell. 2016 Feb 18;61(4):496-505
pubmed: 26895423
DNA Repair (Amst). 2014 Jul;19:84-94
pubmed: 24746923
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Nat Rev Genet. 2012 Jan 24;13(3):189-203
pubmed: 22269907
Nature. 2010 Apr 1;464(7289):721-7
pubmed: 20360735
Oncogene. 2016 Sep 8;35(36):4719-29
pubmed: 26804174
Nat Rev Genet. 2008 Mar;9(3):204-17
pubmed: 18227811
Nat Med. 2016 Sep 7;22(9):976-86
pubmed: 27603132
Am J Physiol Cell Physiol. 2014 Feb 1;306(3):C250-62
pubmed: 24284797
Gastroenterology. 2005 Feb;128(2):424-32
pubmed: 15685553
EMBO Rep. 2014 Sep;15(9):948-55
pubmed: 25092791
Nat Rev Genet. 2012 Feb 14;13(3):204-14
pubmed: 22330764
Nat Rev Cancer. 2015 May;15(5):276-89
pubmed: 25907220
Oncogenesis. 2016 Dec 19;5(12):e280
pubmed: 27991914
Cell Mol Life Sci. 2015 Oct;72(20):3831-51
pubmed: 26089250
Elife. 2014 May 6;:e02028
pubmed: 24842991
Gut. 2005 Feb;54(2):297-302
pubmed: 15647198
ScientificWorldJournal. 2013;2013:597095
pubmed: 23533353
Nat Commun. 2016 Dec 15;7:13887
pubmed: 27976684
Mol Cell. 2015 Feb 19;57(4):636-647
pubmed: 25699710
Cancer Discov. 2018 May;8(5):537-555
pubmed: 29653955
Genes Dev. 1999 Apr 1;13(7):841-50
pubmed: 10197984
Nat Immunol. 2003 May;4(5):442-51
pubmed: 12679812
EMBO J. 2014 Nov 18;33(22):2643-58
pubmed: 25257309
EMBO J. 2016 Mar 15;35(6):635-53
pubmed: 26903600
EMBO J. 1997 Aug 15;16(16):5077-85
pubmed: 9305649
Cancer Res. 2009 Feb 15;69(4):1358-67
pubmed: 19190340
Oncogene. 2013 May 30;32(22):2792-8
pubmed: 22777358
Hepatology. 2015 Jan;61(1):171-83
pubmed: 25132062
Nucleic Acids Res. 2016 Feb 29;44(4):1854-70
pubmed: 26704980
Cell. 2005 Aug 12;122(3):365-78
pubmed: 16096057
Genes (Basel). 2017 Jan 14;8(1):
pubmed: 28098815
Front Genet. 2015 Apr 28;6:166
pubmed: 25972894
EMBO J. 2014 Nov 18;33(22):2623-42
pubmed: 25257310
Mol Cell. 2013 Apr 25;50(2):223-35
pubmed: 23562324
Elife. 2014 Aug 08;3:e03032
pubmed: 25107276
J Clin Invest. 2014 Jul;124(7):2909-20
pubmed: 24865429
Cell. 2010 Nov 24;143(5):737-49
pubmed: 21111234
Nucleus. 2010 Nov-Dec;1(6):447-59
pubmed: 21327086
EMBO J. 2014 Nov 18;33(22):2601-3
pubmed: 25266476
Cancer Res. 2006 Jun 15;66(12):6129-38
pubmed: 16778186
EMBO J. 2017 May 2;36(9):1182-1198
pubmed: 28314779