A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA

Fanconi anemia (FA) is an autosomal recessive disease with congenital anoma lies, bone marrow failure, and susceptibility to leukemia. Patient cells sh ow chromosome instability and hypersensitivity to DNA cross-linking agents. At least 8 complementation groups (A-G) have been identified and 6 FA gene s (for subtypes A, C, D2, E, F, and G) have been cloned. Increasing evidenc e indicates that a protein complex assembly of multiple FA proteins, includ ing FANCA and FANCG, plays a crucial role in the FA pathway. Previously, it was reported that FANCA was phosphorylated in lymphoblasts from normal con trols, whereas the phosphorylation was defective in those derived from pati ents with FA of multiple complementation groups. The present study examined phosphorylation of FANCA ectopically expressed in FANCA(-) cells. Several patient-derived mutations abrogated in vivo phosphorylation of FANCA in thi s system, suggesting that FANCA phosphorylation is associated with its func tion. In vitro phosphorylation studies indicated that a physiologic protein kinase for FANCA (FANCA-PK) forms a complex with the substrate. Furthermor e, at least a part of FANCA-PK as well as phosphorylated FANCA were include d in the FANCA/FANCG complex. Thus, FANCA-PK appears to be another componen t of the FA protein complex and may regulate function of FANCA. FANCA-PK wa s characterized as a cytoplasmic serine kinase sensitive to wortmannin. Ide ntification of the protein kinase Is expected to elucidate regulatory mecha nisms that control the FA pathway. (C) 2001 by The American Society of Hema tology.