title: Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis.
abstract: Fas-associated death domain protein (FADD) is an adaptor protein bridging death receptors with initiator caspases. Thus, its function and localization are assumed to be cytoplasmic, although the localization of endogenous FADD has not been reported. Surprisingly, the data presented here demonstrate that FADD is mainly nuclear in several adherent cell lines. Its accumulation in the nucleus and export to the cytoplasm required the phosphorylation site Ser-194, which was also required for its interaction with the nucleocytoplasmic shuttling protein exportin-5. Within the nucleus, FADD interacted with the methyl-CpG binding domain protein 4 (MBD4), which excises thymine from GT mismatches in methylated regions of chromatin. The MBD4-interacting mismatch repair factor MLH1 was also found in a complex with FADD. The FADD-MBD4 interaction involved the death effector domain of FADD and a region of MBD4 adjacent to the glycosylase domain. The FADD-binding region of MBD4 was downstream of a frameshift mutation that occurs in a significant fraction of human colorectal carcinomas. Consistent with the idea that MBD4 can signal to an apoptotic effector, MBD4 regulated DNA damage-, Fas ligand-, and cell detachment-induced apoptosis. The nuclear localization of FADD and its interaction with a genome surveillance/DNA repair protein that can regulate apoptosis suggests a novel function of FADD distinct from direct participation in death receptor signaling complexes.
authors.affiliation: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
authors.forename: Stephan
authors.initials: S
authors.lastname: Kiessling
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Millar
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maddison
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.forename: Steven M
authors.initials: SM
authors.lastname: Frisch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D016678:Genome; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020931:ran GTP-Binding Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D028884:Karyopherins; C446511:XPO5 protein, human; C499175:Xpo5 protein, mouse; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; C492249:Mbd4 protein, mouse; D020931:ran GTP-Binding Protein