title: BLM promotes the activation of Fanconi Anemia signaling pathway.
abstract: Mutations in the human RecQ helicase, BLM, causes Bloom Syndrome, which is a rare autosomal recessive disorder and characterized by genomic instability and an increased risk of cancer. Fanconi Anemia (FA), resulting from mutations in any of the 19 known FA genes and those yet to be known, is also characterized by chromosomal instability and a high incidence of cancer. BLM helicase and FA proteins, therefore, may work in a common tumor-suppressor signaling pathway. To date, it remains largely unclear as to how BLM and FA proteins work concurrently in the maintenance of genome stability. Here we report that BLM is involved in the early activation of FA group D2 protein (FANCD2). We found that FANCD2 activation is substantially delayed and attenuated in crosslinking agent-treated cells harboring deficient Blm compared to similarly treated control cells with sufficient BLM. We also identified that the domain VI of BLM plays an essential role in promoting FANCD2 activation in cells treated with DNA crosslinking agents, especially ultraviolet B. The similar biological effects performed by ΔVI-BLM and inactivated FANCD2 further confirm the relationship between BLM and FANCD2. Mutations within the domain VI of BLM detected in human cancer samples demonstrate the functional importance of this domain, suggesting human tumorigenicity resulting from mtBLM may be at least partly attributed to mitigated FANCD2 activation. Collectively, our data show a previously unknown regulatory liaison in advancing our understanding of how the cancer susceptibility gene products act in concert to maintain genome stability.
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors.forename: Jayabal
authors.initials: J
authors.lastname: Panneerselvam
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.|Current address: Sun Yat-Sen University, Guangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Che
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Fei
mesh_terms: D001816:Bloom Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005199:Fanconi Anemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D052240:Fanconi Anemia Complementation Group L Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D053484:RecQ Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D003432:Cross-Linking Reagents; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: BLM; DNA damage; FANCD2 monoubiquitination; Fanconi Anemia; tumorigenesis