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.
authors.affiliation: 1] Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, Institute of Diagnostics, University of Oulu and Oulu University Hospital, 90220 Oulu, Finland [2] [3].
authors.forename: Jenni
authors.initials: J
authors.lastname: Nikkilä
authors.forename: Ann Christin
authors.initials: AC
authors.lastname: Parplys
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Muthiah
authors.initials: M
authors.lastname: Bose
authors.forename: Yanying
authors.initials: Y
authors.lastname: Huo
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.forename: Pentti
authors.initials: P
authors.lastname: Nieminen
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Helmut
authors.initials: H
authors.lastname: Pospiech
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D043171:Chromosomal Instability; D004249:DNA Damage; D004261:DNA Replication; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1