Our recent work has focused on the roles of the FANCJ helicase in the DNA damage response. Mutations in the BRCA1-associated helicase BACH1 have been associated with early-onset breast cancer and cellular data suggest a role of the helicase in double strand break repair and checkpoint control. Recently, BACH1 (FANCJ) has been genetically linked to the chromosomal instability disorder Fanconi anemia (FA). To understand the molecular functions and biological substrates that FANCJ helicase acts upon, we have systematically evaluated the ability of purified recombinant FANCJ to unwind a panel of related DNA substrates with distinct tail variations including single-stranded versus double-stranded character, tail length, or backbone continuity. In addition, we have assessed the ability of BACH1 to catalytically unwind DNA structures proposed to be key intermediates of cellular DNA metabolism. The results from these unwinding studies provide a platform to investigate the molecular interactions of the FANCJ helicase with its protein partners in double strand break repair by homologous recombination. In terms of protein interactions, we have identified and characterized two novel FANCJ partners, the mismatch repair protein complex MutL alpha and the single-stranded DNA binding protein RPA. FANCJ interactions with these DNA repair factors play important roles in the DNA damage response. Our current efforts are directed toward understanding the roles of FANCJ in the classic FA pathway of cross-link repair as well as stabilization and progression of the replication fork.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000753-03
Application #
8148314
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2010
Total Cost
$198,056
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Bharti, Sanjay Kumar; Sommers, Joshua A; Awate, Sanket et al. (2018) A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair. Nucleic Acids Res 46:6238-6256
Datta, Arindam; Brosh Jr, Robert M (2018) New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy. Front Mol Biosci 5:59
Estep, Katrina N; Brosh Jr, Robert M (2018) RecQ and Fe-S helicases have unique roles in DNA metabolism dictated by their unwinding directionality, substrate specificity, and protein interactions. Biochem Soc Trans 46:77-95
Estep, Katrina N.; Butler, Thomas J.; Ding, Jun et al. (2017) G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets. Curr Med Chem :
Brosh Jr, Robert M; Bellani, Marina; Liu, Yie et al. (2017) Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging. Ageing Res Rev 33:67-75
Brosh Jr, Robert M (2017) Editorial. Ageing Res Rev 33:1-2
Henderson, Alexander; Wu, Yuliang; Huang, Yu Chuan et al. (2017) Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res 45:6252
Awate, Sanket; Brosh Jr, Robert M (2017) Interactive Roles of DNA Helicases and Translocases with the Single-Stranded DNA Binding Protein RPA in Nucleic Acid Metabolism. Int J Mol Sci 18:
Crouch, Jack D; Brosh Jr, Robert M (2017) Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism. Free Radic Biol Med 107:245-257
Calì, Federica; Bharti, Sanjay Kumar; Di Perna, Roberta et al. (2016) Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway. Nucleic Acids Res 44:705-17

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