Format

Send to

Choose Destination
Nat Commun. 2013;4:2578. doi: 10.1038/ncomms3578.

Heterozygous mutations in PALB2 cause DNA replication and damage response defects.

Author information

1
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].

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.

PMID:
24153426
PMCID:
PMC3826652
DOI:
10.1038/ncomms3578
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center