Heterozygous mutations in PALB2 cause DNA replication and damage response defects
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Heterozygous mutations in PALB2 cause DNA replication and damage response defects. / Nikkilä, Jenni; Parplys, Ann Christin; Pylkäs, Katri; Bose, Muthiah; Huo, Yanying; Borgmann, Kerstin; Rapakko, Katrin; Nieminen, Pentti; Xia, Bing; Pospiech, Helmut; Winqvist, Robert.
in: NAT COMMUN, Jahrgang 4, 01.01.2013, S. 2578.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Heterozygous mutations in PALB2 cause DNA replication and damage response defects
AU - Nikkilä, Jenni
AU - Parplys, Ann Christin
AU - Pylkäs, Katri
AU - Bose, Muthiah
AU - Huo, Yanying
AU - Borgmann, Kerstin
AU - Rapakko, Katrin
AU - Nieminen, Pentti
AU - Xia, Bing
AU - Pospiech, Helmut
AU - Winqvist, Robert
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition.
AB - Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition.
KW - Ataxia Telangiectasia Mutated Proteins
KW - BRCA1 Protein
KW - BRCA2 Protein
KW - Breast Neoplasms
KW - Case-Control Studies
KW - Cell Line, Tumor
KW - Checkpoint Kinase 2
KW - Chromosomal Instability
KW - DNA Damage
KW - DNA Replication
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Genetic Predisposition to Disease
KW - Haploinsufficiency
KW - Heterozygote
KW - Humans
KW - Lymphocytes
KW - Mutation
KW - Nuclear Proteins
KW - Primary Cell Culture
KW - Protein Kinases
KW - Tumor Suppressor Proteins
U2 - 10.1038/ncomms3578
DO - 10.1038/ncomms3578
M3 - SCORING: Journal article
C2 - 24153426
VL - 4
SP - 2578
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -