The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair

Wendy L. Bridge, Cassandra J. Vandenberg, Roger J. Franklin, Kevin Hiom (Lead / Corresponding author)

    Research output: Contribution to journalLetterpeer-review

    160 Citations (Scopus)

    Abstract

    BRIP1 (also called BACH1) is a DEAH helicase that interacts with the BRCT domain of BRCA1 (refs. 1-6) and has an important role in BRCA1-dependent DNA repair and checkpoint functions. We cloned the chicken ortholog of BRIP1 and established a homozygous knockout in the avian B-cell line DT40. The phenotype of these brip1 mutant cells in response to DNA damage differs from that of brca1 mutant cells and more closely resembles that of fancc mutant cells, with a profound sensitivity to the DNA-crosslinking agent cisplatin and acute cell-cycle arrest in late S-G2 phase. These defects are corrected by expression of human BRIP1 lacking the BRCT-interaction domain. Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knock-down of BRIP1 leads to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia. Because brip1 mutant cells are proficient for ubiquitination of FANCD2 protein, our data indicate that BRIP1 has a function in the Fanconi anemia pathway that is independent of BRCA1 and downstream of FANCD2 activation.

    Original languageEnglish
    Pages (from-to)953-957
    Number of pages5
    JournalNature Genetics
    Volume37
    Issue number9
    DOIs
    Publication statusPublished - Sep 2005

    Keywords

    • Animals
    • BRCA1 protein
    • Chickens
    • Chromosome aberrations
    • Cisplatin
    • Cross-linking reagents
    • DNA damage
    • DNA repair
    • DNA-binding proteins
    • Fanconi anemia
    • Fanconi anemia complementation group D2 protein
    • G2 phase
    • HeLa cells
    • Humans
    • Mitomycin
    • Nuclear proteins
    • RNA helicases
    • RNA, Small interfering
    • S phase
    • Signal transduction
    • Ubiquitin

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