The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

Cantor, Sharon B.; Drapkin, Ronny; Zhang, Fan; Lin, Yu-Hua; Han, Juliana; Pamidi, Sushmita; Livingston, David M.

doi:10.1073/pnas.0308717101

Cited by 219 publications

(264 citation statements)

References 43 publications

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“…Recombinant Proteins-Baculovirus encoding FANCJ with a C-terminal FLAG tag was used to infect High Five insect cells, and the recombinant FANCJ protein was purified as described previously (10). Purified recombinant FANCJ protein predominantly migrated as a single band of the predicted size (130 kDa) on an SDS-polyacrylamide gel, as reported previously (10).…”

Section: Methodsmentioning

confidence: 99%

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FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

Suhasini

Sommers

Mason

et al. 2009

Journal of Biological Chemistry

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FANCJ mutations are genetically linked to the Fanconi anemia complementation group J and predispose individuals to breast cancer. Understanding the role of FANCJ in DNA metabolism and how FANCJ dysfunction leads to tumorigenesis requires mechanistic studies of FANCJ helicase and its protein partners. In this work, we have examined the ability of FANCJ to unwind DNA molecules with specific base damage that can be mutagenic or lethal. FANCJ was inhibited by a single thymine glycol, but not 8-oxoguanine, in either the translocating or nontranslocating strands of the helicase substrate. In contrast, the human RecQ helicases (BLM, RECQ1, and WRN) display strand-specific inhibition of unwinding by the thymine glycol damage, whereas other DNA helicases (DinG, DnaB, and UvrD) are not significantly inhibited by thymine glycol in either strand. In the presence of replication protein A (RPA), but not Escherichia coli single-stranded DNA-binding protein, FANCJ efficiently unwound the DNA substrate harboring the thymine glycol damage in the nontranslocating strand; however, inhibition of FANCJ helicase activity by the translocating strand thymine glycol was not relieved. Strand-specific stimulation of human RECQ1 helicase activity was also observed, and RPA bound with high affinity to single-stranded DNA containing a single thymine glycol. Based on the biochemical studies, we propose a model for the specific functional interaction between RPA and FANCJ on the thymine glycol substrates. These studies are relevant to the roles of RPA, FANCJ, and other DNA helicases in the metabolism of damaged DNA that can interfere with basic cellular processes of DNA metabolism. Fanconi anemia (FA)2 is an autosomal recessive disorder characterized by multiple congenital anomalies, progressive bone marrow failure, and high cancer risk (1-3). Cells from FA patients exhibit spontaneous chromosomal instability and hypersensitivity to agents that induce DNA interstrand crosslinks. Although the precise mechanistic details of the FA pathway of interstrand cross-link-repair are not well understood, progress has been made in the identification of the FA proteins that are required for the pathway (1-3). Among the 13 FA complementation groups from which all FA genes have been cloned, only a few of the FA proteins are predicted to have direct roles in DNA metabolism. One of the more recently identified FA proteins shown to be responsible for complementation of the FA complementation group J is FANCJ (4 -6). FANCJ was originally designated BACH1 (BRCA1-associated C-terminal helicase), which was discovered by Cantor et al. (7) as a protein that binds to the BRCT repeats of BRCA1. A genetic interaction between FANCJ and BRCA1 in double strand break repair was established (7), and FANCJ mutations were identified in early onset breast cancer (7-9), suggesting a tumor suppressor role of FANCJ.FANCJ was first shown to be a DNA-dependent ATPase that catalytically unwinds duplex DNA with a 5Ј to 3Ј directionality (10). Consistent with its directionality, FANCJ r...

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Section: Methodsmentioning

confidence: 99%

“…FANCJ was first shown to be a DNA-dependent ATPase that catalytically unwinds duplex DNA with a 5Ј to 3Ј directionality (10). Consistent with its directionality, FANCJ requires nucleic acid continuity in the 5Ј-ssDNA tail near the ssDNA-dsDNA junction of the forked duplex substrate to efficiently initiate DNA unwinding (11).…”

mentioning

confidence: 99%

FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

Suhasini

Sommers

Mason

et al. 2009

Journal of Biological Chemistry

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“…Carriers of mutations in BRCA1 or BRCA2/ FANCD1 have an 82% lifetime risk of breast cancer and a 54% and 23% risk of ovarian cancer, respectively (King et al 2003). Mutations in FANCJ (BRIP1) have also been identified in patients with early onset breast cancer (Cantor et al 2004) although the lifetime risk is unknown. This observation suggests that the FA pathway is important in the prevention of these female cancers and that unidentified mutations of other FA genes may account for some familial breast/ovarian cancer pedigrees not accounted for by BRCA1 or BRCA2/FANCD1.…”

Section: Cancer Risk In Heterozygous Carriers Of Fa Gene Mutationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

362

345

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Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

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“…The BRCT repeats of BRCA1 are implicated in regulated interactions with certain phosphorylated proteins [118,119], including BACH1/FANCJ, a BRCA1-interacting DEAHtype 5′-to-3′ DNA helicase [120,121], and CtIP, a transcriptional repressor with DNA damage checkpoint functions [122,123]. Certain point mutant disease-predisposing alleles of BRCA1 disrupt these interactions, indicating that these interactions are clinically relevant.…”

Section: Molecular Functions Of Brca1 and Brca2mentioning

confidence: 99%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations

Cited by 219 publications

References 43 publications

FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

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