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The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.

ABSTRACT: Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN1), an essential enzyme involved in DNA replication and repair, can lead to functional deficiencies of the FEN1 protein and a predisposition to cancer. We identified a FEN1 germline mutation that changed residue E359 to K in a patient whose family had a history of breast cancer. We determined that the E359K mutation, which is in the protein-protein domain of FEN1, abolished the interaction of FEN1 with Werner syndrome protein (WRN), an interaction that is critical for resolving stalled DNA replication forks. Furthermore, although the flap endonuclease activity of FEN1 E359K was unaffected, it failed to resolve bubble structures, which require the FEN1 gap-dependent endonuclease activity. To determine the etiological significance of E359K, we established a mouse model containing this mutation. E359K mouse embryonic fibroblasts (MEF) were more sensitive to DNA crosslinking agents that cause replication forks to stall. Cytological analysis suggested that the FEN1-WRN interaction was also required for telomere stability; mutant cell lines had fragile telomeres, increased numbers of spontaneous chromosomal anomalies and higher frequencies of transformation. Moreover, the incidence of cancer was significantly higher in mice homozygous for FEN1 E359K than in wild-type mice, suggesting that the FEN1 E359K mutation is oncogenic.

SUBMITTER: Chung L

PROVIDER: S-EPMC4160428 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.

Chung L L Onyango D D Guo Z Z Jia P P Dai H H Liu S S Zhou M M Lin W W Pang I I Li H H Yuan Y-C YC Huang Q Q Zheng L L Lopes J J Nicolas A A Chai W W Raz D D Reckamp K L KL Shen B B

Oncogene 20140310 7

Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN1), an essential enzyme involved in DNA replication and repair, can lead to functional deficiencies of the FEN1 protein and a predisposition to cancer. We identified a FEN1 germline mutation that changed residue E359 to K in a patient whose family had a history of breast cancer. We determined that the E359K mutation, which is in the protein-protein domain of FEN1, abolished the interaction of FEN1 with Werner syndrome protein (WRN), ...[more]

PMID: 24608430

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Project description:Background:A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods:We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results:We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion:The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

Dataset Information

The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.

Publications

The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.

Similar Datasets

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