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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, Vol. 4, 01.01.2013, p. 2578.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Nikkilä, J, Parplys, AC, Pylkäs, K, Bose, M, Huo, Y, Borgmann, K, Rapakko, K, Nieminen, P, Xia, B, Pospiech, H & Winqvist, R 2013, 'Heterozygous mutations in PALB2 cause DNA replication and damage response defects', NAT COMMUN, vol. 4, pp. 2578. https://doi.org/10.1038/ncomms3578

APA

Nikkilä, J., Parplys, A. C., Pylkäs, K., Bose, M., Huo, Y., Borgmann, K., Rapakko, K., Nieminen, P., Xia, B., Pospiech, H., & Winqvist, R. (2013). Heterozygous mutations in PALB2 cause DNA replication and damage response defects. NAT COMMUN, 4, 2578. https://doi.org/10.1038/ncomms3578

Vancouver

Nikkilä J, Parplys AC, Pylkäs K, Bose M, Huo Y, Borgmann K et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. NAT COMMUN. 2013 Jan 1;4:2578. https://doi.org/10.1038/ncomms3578

Bibtex

@article{457fd40d1e984c638975ddfbedde7b95,
title = "Heterozygous mutations in PALB2 cause DNA replication and damage response defects",
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.",
keywords = "Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Checkpoint Kinase 2, Chromosomal Instability, DNA Damage, DNA Replication, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Humans, Lymphocytes, Mutation, Nuclear Proteins, Primary Cell Culture, Protein Kinases, Tumor Suppressor Proteins",
author = "Jenni Nikkil{\"a} and Parplys, {Ann Christin} and Katri Pylk{\"a}s and Muthiah Bose and Yanying Huo and Kerstin Borgmann and Katrin Rapakko and Pentti Nieminen and Bing Xia and Helmut Pospiech and Robert Winqvist",
year = "2013",
month = jan,
day = "1",
doi = "10.1038/ncomms3578",
language = "English",
volume = "4",
pages = "2578",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",

}

RIS

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 -