Academic Journal
Προβολή σε EDS

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress.
Συγγραφείς: Bleuyard JY; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom., Fournier M; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom., Nakato R; Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0032, Japan., Couturier AM; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom., Katou Y; Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0032, Japan., Ralf C; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom., Hester SS; Advanced Proteomics Facility, Department of Biochemisty, University of Oxford, Oxford, OX1 3QU, United Kingdom., Dominguez D; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139-4307., Rhodes D; NTU Institute of Structural Biology, Nanyang Technological University, 636921 Singapore., Humphrey TC; Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom., Shirahige K; Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0032, Japan., Esashi F; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom; fumiko.esashi@path.ox.ac.uk.
Πηγή: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jul 18; Vol. 114 (29), pp. 7671-7676. Date of Electronic Publication: 2017 Jul 03.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, DC : National Academy of Sciences
Ιατρικοί όροι (MeSH): DNA Damage*, Chromatin/*ultrastructure , Fanconi Anemia Complementation Group N Protein/*metabolism , Histone-Lysine N-Methyltransferase/*metabolism , Transcription Factors/*metabolism, BRCA2 Protein/genetics ; Chromosomes/ultrastructure ; Tumor Suppressor Proteins/metabolism ; Cell Line, Tumor ; DNA Repair ; DNA Replication ; Genome, Human ; HEK293 Cells ; HeLa Cells ; Humans ; Inhibitory Concentration 50 ; Mutation ; Protein Binding ; Proteomics ; Transcription, Genetic
Περίληψη: The partner and localiser of BRCA2 (PALB2) plays important roles in the maintenance of genome integrity and protection against cancer. Although PALB2 is commonly described as a repair factor recruited to sites of DNA breaks, recent studies provide evidence that PALB2 also associates with unperturbed chromatin. Here, we investigated the previously poorly described role of chromatin-associated PALB2 in undamaged cells. We found that PALB2 associates with active genes through its major binding partner, MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) by the SETD2 methyltransferase. Missense mutations that ablate PALB2 binding to MRG15 confer elevated sensitivity to the topoisomerase inhibitor camptothecin (CPT) and increased levels of aberrant metaphase chromosomes and DNA stress in gene bodies, which were suppressed by preventing DNA replication. Remarkably, the level of PALB2 at genic regions was frequently decreased, rather than increased, upon CPT treatment. We propose that the steady-state presence of PALB2 at active genes, mediated through the SETD2/H3K36me3/MRG15 axis, ensures an immediate response to DNA stress and therefore effective protection of these regions during DNA replication. This study provides a conceptual advance in demonstrating that the constitutive chromatin association of repair factors plays a key role in the maintenance of genome stability and furthers our understanding of why PALB2 defects lead to human genome instability syndromes.
Competing Interests: The authors declare no conflict of interest.
References: Nat Genet. 2007 Feb;39(2):165-7. (PMID: 17200668)
J Cell Sci. 2010 May 1;123(Pt 9):1395-400. (PMID: 20356927)
Nature. 2007 Mar 15;446(7133):316-9. (PMID: 17287723)
Nature. 2015 Dec 17;528(7582):422-6. (PMID: 26649820)
Nat Genet. 2007 Feb;39(2):159-61. (PMID: 17200672)
J Biol Chem. 2005 Oct 21;280(42):35261-71. (PMID: 16118227)
EMBO J. 2014 Apr 16;33(8):890-905. (PMID: 24591564)
Cancer Res. 2006 May 15;66(10):5181-9. (PMID: 16707442)
Mol Cell. 2015 Sep 17;59(6):998-1010. (PMID: 26365379)
Nat Rev Cancer. 2006 Oct;6(10):789-802. (PMID: 16990856)
Cell. 2006 May 5;125(3):467-81. (PMID: 16603238)
Nature. 2010 Oct 7;467(7316):678-83. (PMID: 20729832)
Cell. 2006 Dec 29;127(7):1361-73. (PMID: 17190600)
Nucleic Acids Res. 2006;34(22):6621-8. (PMID: 17135209)
Elife. 2014 May 06;3:e02482. (PMID: 24843002)
Cell Rep. 2016 Apr 12;15(2):300-9. (PMID: 27050524)
Mol Cell. 2002 Jun;9(6):1191-200. (PMID: 12086617)
Mol Cancer Res. 2009 Jul;7(7):1110-8. (PMID: 19584259)
Cancer Cell. 2015 Nov 9;28(5):557-68. (PMID: 26602815)
Structure. 2015 Jun 2;23(6):1049-57. (PMID: 25960410)
Nat Cell Biol. 2009 Nov;11(11):1315-24. (PMID: 19838172)
EMBO Rep. 2012 Feb 01;13(2):135-41. (PMID: 22193777)
Nature. 2016 Jun 30;534(7609):714-718. (PMID: 27338793)
J Cell Biol. 2015 Mar 2;208(5):563-79. (PMID: 25733714)
Genome Biol. 2008;9(9):R137. (PMID: 18798982)
J Mol Biol. 2012 Sep 28;422(4):519-31. (PMID: 22728643)
J Biol Chem. 2009 Aug 7;284(32):21127-31. (PMID: 19553677)
EMBO J. 1994 Dec 1;13(23):5764-71. (PMID: 7988572)
Nat Struct Mol Biol. 2010 Oct;17(10):1260-2. (PMID: 20729859)
Genome Biol. 2009;10(3):R25. (PMID: 19261174)
Cell Rep. 2014 Jun 26;7(6):2006-18. (PMID: 24931610)
Genes Cells. 2013 Jul;18(7):589-601. (PMID: 23672187)
EMBO J. 2008 Jan 23;27(2):406-20. (PMID: 18157086)
BMC Bioinformatics. 2015 Nov 21;16:392. (PMID: 26589438)
Nat Genet. 2007 Feb;39(2):162-4. (PMID: 17200671)
Genes Dev. 2008 Dec 15;22(24):3422-34. (PMID: 19141475)
Science. 2016 May 13;352(6287):844-9. (PMID: 27174990)
Mol Cell Proteomics. 2008 Apr;7(4):631-44. (PMID: 18029349)
Cell Rep. 2014 Jun 12;7(5):1547-59. (PMID: 24835992)
EMBO Rep. 2009 Sep;10(9):990-6. (PMID: 19609323)
J Biol Chem. 2009 Jul 3;284(27):18302-10. (PMID: 19423707)
Mol Cell. 2006 Jun 23;22(6):719-29. (PMID: 16793542)
J Cell Sci. 2010 Apr 1;123(Pt 7):1124-30. (PMID: 20332121)
Cell Res. 2016 Aug;26(8):946-62. (PMID: 27364684)
Science. 2009 Apr 10;324(5924):217. (PMID: 19264984)
Curr Biol. 2009 Mar 24;19(6):524-9. (PMID: 19268590)
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60. (PMID: 19369211)
Nat Struct Mol Biol. 2014 Apr;21(4):366-74. (PMID: 24658350)
Cancer Cell. 2012 Jul 10;22(1):106-16. (PMID: 22789542)
Nat Struct Mol Biol. 2010 Oct;17(10):1263-5. (PMID: 20729858)
Methods. 2006 Dec;40(4):303-11. (PMID: 17101441)
Grant Information: 101009 United Kingdom WT_ Wellcome Trust; MC_PC_12001 United Kingdom MRC_ Medical Research Council; MC_U142784382 United Kingdom MRC_ Medical Research Council; MC_PC_12003 United Kingdom MRC_ Medical Research Council; MC_UU_00001/4 United Kingdom MRC_ Medical Research Council; MC-PC-12001 United Kingdom MRC_ Medical Research Council
Contributed Indexing: Keywords: DNA replication; MRG15; PALB2; SETD2; transcription
Substance Nomenclature: 0 (BRCA2 Protein)
0 (BRCA2 protein, human)
0 (Chromatin)
0 (Fanconi Anemia Complementation Group N Protein)
0 (MORF4L1 protein, human)
0 (PALB2 protein, human)
0 (Transcription Factors)
0 (Tumor Suppressor Proteins)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.1.1.43 (SETD2 protein, human)
Entry Date(s): Date Created: 20170705 Date Completed: 20180608 Latest Revision: 20250530
Update Code: 20260130
PubMed Central ID: PMC5530651
DOI: 10.1073/pnas.1620208114
PMID: 28673974
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1091-6490
DOI:10.1073/pnas.1620208114