Heterozygous mutations in PALB2 cause DNA replication and damage response defects

Jenni Nikkilä, Ann Christin Parplys, Katri Pylkäs, Muthiah Bose, Yanying Huo, Kerstin Borgmann, Katrin Rapakko, Pentti Nieminen, Bing Xia, Helmut Pospiech () and Robert Winqvist ()
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Jenni Nikkilä: Laboratory of Cancer Genetics and Tumor Biology, Institute of Diagnostics, University of Oulu and Oulu University Hospital
Ann Christin Parplys: Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Center Hamburg-Eppendorf
Katri Pylkäs: Laboratory of Cancer Genetics and Tumor Biology, Institute of Diagnostics, University of Oulu and Oulu University Hospital
Muthiah Bose: Laboratory of Cancer Genetics and Tumor Biology, Institute of Diagnostics, University of Oulu and Oulu University Hospital
Yanying Huo: Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey
Kerstin Borgmann: Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Center Hamburg-Eppendorf
Katrin Rapakko: Northern Finland Laboratory Centre NordLab, Oulu University Hospital, and Institute of Diagnostics, University of Oulu
Pentti Nieminen: Medical Informatics and Statistics Research Group, University of Oulu
Bing Xia: Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey
Helmut Pospiech: University of Oulu
Robert Winqvist: Laboratory of Cancer Genetics and Tumor Biology, Institute of Diagnostics, University of Oulu and Oulu University Hospital

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3578

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