Analysis of the DNA Substrate Specificity of the Human BACH1 HelicaseAssociated with BreastCancer
Open accessAbstract
We have investigated the DNA substrate specificity of BACH1 (BRCA1-associated C-terminal helicase). The importance of various DNA structural elements for efficient unwinding by purified recombinant BACH1 helicase was examined. The results indicated that BACH1 preferentially binds and unwinds a forked duplex substrate compared with a duplex flanked by only one single-stranded DNA (ssDNA) tail. In support of its DNA substrate preference, helicase sequestration studies revealed that BACH1 can be preferentially trapped by forked duplex molecules. BACH1 helicase requires a minimal 5 ' ssDNA tail of 15 nucleotides for unwinding of conventional duplex DNA substrates; however, the enzyme is able to catalytically release the third strand of the homologous recombination intermediate D-loop structure irrespective of DNA tail status. In contrast, BACH1 completely fails to unwind a synthetic Holliday junction structure. Moreover, BACH1 requires nucleic acid continuity in the 5 ' ssDNA tail of the forked duplex substrate within six nucleotides of the ssDNA-dsDNA junction to initiate efficiently DNA unwinding. These studies provide the first detailed information on the DNA substrate specificity of BACH1 helicase and provide insight to the types of DNA structures the enzyme is likely to act upon to perform its functions in DNA repair or recombination.
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FANCJ preferentially binds and unwinds forked duplex DNA substrates and D-loop structures that mimic a homologous recombination intermediate.
“Moreover, it was determined that FANCJ preferentially binds and unwinds forked duplex DNA substrates as well as D-loop structures that mimic an intermediate step in homologous recombination [61].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [61]
The ATPase and helicase functions of FANCJ are inactivated by the K52R missense mutation in the ATP-binding pocket.
“As predicted, the ATPase and helicase functions were inactivated by a single missense mutation (K52R) in the ATP-binding pocket of the FANCJ helicase domain [56,61,62].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [61]
The P47A FANCJ mutant has disrupted enzyme activity.
“The P47A mutant had disrupted enzyme activity”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [61]
The M299I FANCJ mutant has enhanced ATPase, helicase, and translocase activity.
“the M299I mutant had enhanced ATPase, helicase and translocase activity [56,61]”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [61]
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Helicase-inactivating mutations as a basis for dominant negative phenotypes
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Self-citationFANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses
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Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair
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Self-citationEstep, K. N., & Brosh, R. M. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170044 · Cited by 29 · see citing works
Self-citationCheng, Z., Caillet, A., Ren, B., & Ding, H. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.09.032 · Cited by 29 · see citing works
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Self-citationFANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation
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Self-citationCancer Therapy and Replication Stress
Kotsantis, P., Jones, R. M., Higgs, M. R., & Petermann, E. (2015) · Advances in clinical chemistry · doi:10.1016/bs.acc.2014.12.003 · Cited by 24 · see citing works
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An emerging picture of FANCJ’s role in G4 resolution to facilitate DNA replication
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Self-citationMechanistic and biological aspects of helicase action on damaged DNA
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Self-citationSuhasini, A. N., Sommers, J. A., Yu, S. W., Wu, Y., Xu, T., Kelman, Z., Kaplan, D. L., & Brosh, R. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.352757 · Cited by 23 · see citing works
Self-citationBiochemical Characterization of the Human Mitochondrial Replicative Twinkle Helicase
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Self-citationImpact of Age-Associated Cyclopurine Lesions on DNA Repair Helicases
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Self-citationFancJ/Brip1 helicase protects against genomic losses and gains in vertebrate cells
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RegNetB: Predicting Relevant Regulator-Gene Relationships in Localized Prostate Tumor Samples
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HP1 regulates the localization of FANCJ at sites of DNA double‐strand breaks
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Crouch, J. D., & Brosh, R. M. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.11.022 · Cited by 15 · see citing works
Self-citationThe role of the Fanconi anemia network in the response to DNA replication stress
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Self-citationMutational analysis of FANCJ helicase
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Close encounters for the first time: Helicase interactions with DNA damage
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Self-citationBLM’s balancing act and the involvement of FANCJ in DNA repair
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Self-citationDNA repair helicases: from mechanistic understanding to therapeutic implications
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Assembling an orchestra: Fanconi anemia pathway of repair
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The repair gene BACH1 - a potential oncogene
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Self-citationHow DNA secondary structures drive replication fork instability
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- Authors
- Gupta, R., Sharma, S., Sommers, J. A., Jin, Z., Cantor, S. B., & Brosh, R. M.
- Affiliations
- National Institutes of Health (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Brosh, Robert M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 27
- Pages
- 25450-25460
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1986550902
- Cited by
- 131
- References
- 31
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- DNA unwinding, homologous recombination, Holliday junction, DNA repair, breast cancer
- MeSH terms
- Breast Neoplasms, DNA, DNA Helicases, DNA, Single-Stranded, Enzyme Activation, Humans, Nucleic Acid Conformation, Substrate Specificity, Transcription Factors, DNA, Cruciform, Basic-Leucine Zipper Transcription Factors, Fanconi Anemia Complementation Group Proteins
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