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

[werner syndrome]

Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN 1 ), an essential enzyme involved in DNA replication and repair , can lead to functional deficiencies of the FEN 1 protein and a predisposition to cancer . We identified a FEN 1 germline mutation that changed residue E 359 to K in a patient whose family had a history of breast cancer . We determined that the E 359 K mutation , which is in the protein-protein domain of FEN 1 , abolished the interaction of FEN 1 with Werner syndrome protein (WRN ), an interaction that is critical for resolving stalled DNA replication forks . Furthermore , although the flap endonuclease activity of FEN 1 E 359 K was unaffected , it failed to resolve bubble structures , which require the FEN 1 gap-dependent endonuclease activity . To determine the etiological significance of E 359 K , we established a mouse model containing this mutation . E 359 K mouse embryonic fibroblasts (MEF ) were more sensitive to DNA crosslinking agents that cause replication forks to stall . Cytological analysis suggested that the FEN 1 -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 FEN 1 E 359 K than in wild-type mice , suggesting that the FEN 1 E 359 K mutation is oncogenic .Oncogene advance online publication , 10 March 2014 ; doi :10 .1038 /onc .2014 .19 .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated