Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2.
Animals
Breast Neoplasms
/ genetics
DNA, Complementary
Fanconi Anemia Complementation Group N Protein
/ genetics
Flow Cytometry
Genetic Predisposition to Disease
Genetic Techniques
Genomic Instability
Humans
Mice
Mice, Knockout
Mouse Embryonic Stem Cells
/ metabolism
Mutant Proteins
/ metabolism
Mutation, Missense
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 11 2019
22 11 2019
Historique:
received:
05
04
2019
accepted:
25
10
2019
entrez:
24
11
2019
pubmed:
24
11
2019
medline:
3
3
2020
Statut:
epublish
Résumé
Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.
Identifiants
pubmed: 31757951
doi: 10.1038/s41467-019-13194-2
pii: 10.1038/s41467-019-13194-2
pmc: PMC6876638
doi:
Substances chimiques
DNA, Complementary
0
Fanconi Anemia Complementation Group N Protein
0
Mutant Proteins
0
PALB2 protein, human
0
Palb2 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5296Subventions
Organisme : CIHR
Pays : Canada
Commentaires et corrections
Type : CommentIn
Références
Trends Biochem Sci. 2019 Mar;44(3):226-240
pubmed: 30638972
Nat Genet. 2007 Feb;39(2):159-61
pubmed: 17200672
Oncogene. 2019 Mar;38(10):1585-1596
pubmed: 30337689
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
J Clin Invest. 2009 Oct;119(10):3160-71
pubmed: 19770520
Cancer Res. 2017 Jun 1;77(11):2789-2799
pubmed: 28283652
Int J Cancer. 2017 Jan 1;140(1):95-102
pubmed: 27616075
Genet Med. 2019 Feb;21(2):293-302
pubmed: 29988080
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Am J Hum Genet. 2016 Oct 6;99(4):877-885
pubmed: 27666373
Nat Genet. 2017 Oct;49(10):1476-1486
pubmed: 28825726
Nature. 2018 Aug;560(7716):117-121
pubmed: 30022168
Am J Hum Genet. 2003 May;72(5):1117-30
pubmed: 12677558
Oncogene. 2014 Oct 2;33(40):4803-12
pubmed: 24141787
J Med Genet. 2016 Dec;53(12):800-811
pubmed: 27595995
NPJ Breast Cancer. 2019 Aug 8;5:23
pubmed: 31428676
Mol Cell. 2006 Jun 23;22(6):719-729
pubmed: 16793542
Am J Hum Genet. 2018 Oct 4;103(4):498-508
pubmed: 30219179
Nat Med. 2008 Aug;14(8):875-81
pubmed: 18607349
Gene. 1991 Dec 15;108(2):193-9
pubmed: 1660837
Mol Cell. 2001 Feb;7(2):263-72
pubmed: 11239455
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5564-9
pubmed: 23509290
Science. 2015 Nov 27;350(6264):1092-6
pubmed: 26472760
N Engl J Med. 2014 Aug 7;371(6):497-506
pubmed: 25099575
J Pathol. 2011 May;224(1):10-21
pubmed: 21404276
Genet Med. 2016 Aug;18(8):823-32
pubmed: 26681312
EMBO Rep. 2011 Jul 01;12(7):705-12
pubmed: 21637299
JAMA Oncol. 2017 Sep 1;3(9):1190-1196
pubmed: 28418444
Genes Dev. 1998 Jun 1;12(11):1599-609
pubmed: 9620848
J Med Genet. 2006 Apr;43(4):295-305
pubmed: 16014699
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60
pubmed: 19369211
Nucleic Acids Res. 2017 Mar 17;45(5):2644-2657
pubmed: 28158555
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W452-7
pubmed: 22689647
Curr Biol. 2009 Mar 24;19(6):524-9
pubmed: 19268590
Cancer Discov. 2013 Oct;3(10):1142-55
pubmed: 23867111
Cancer Res. 2001 May 15;61(10):4092-7
pubmed: 11358831
Nature. 2015 Feb 12;518(7538):258-62
pubmed: 25642963
Nat Genet. 2007 Feb;39(2):162-4
pubmed: 17200671
Mol Cancer Res. 2009 Jul;7(7):1110-8
pubmed: 19584259
Oncogene. 2017 Jul 20;36(29):4161-4170
pubmed: 28319063
Cancer Res. 1998 Aug 1;58(15):3193-6
pubmed: 9699640
Nat Genet. 2007 Feb;39(2):165-7
pubmed: 17200668
J Biol Chem. 2014 Aug 29;289(35):24617-29
pubmed: 25016020
EMBO J. 2016 May 2;35(9):909-23
pubmed: 27037238
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Nature. 2018 Oct;562(7726):217-222
pubmed: 30209399
EMBO Rep. 2009 Sep;10(9):990-6
pubmed: 19609323
Genesis. 2010 Aug;48(8):512-20
pubmed: 20506501
EMBO Rep. 2012 Feb 01;13(2):135-41
pubmed: 22193777
Hum Mol Genet. 2010 Aug 1;19(15):3021-9
pubmed: 20484223
Nat Struct Mol Biol. 2010 Oct;17(10):1247-54
pubmed: 20871615
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Nat Genet. 2018 Jun;50(6):874-882
pubmed: 29785012
Science. 2011 Jun 10;332(6035):1313-7
pubmed: 21659603