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 #
1ZIAAG000753-06
Application #
8736613
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$273,943
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Bharti, Sanjay Kumar; Brosh Jr, Robert M (2016) Fine-tuning DNA repair by protein acetylation. Cell Cycle 15:1952-3
Bharti, Sanjay Kumar; Awate, Sanket; Banerjee, Taraswi et al. (2016) Getting Ready for the Dance: FANCJ Irons Out DNA Wrinkles. Genes (Basel) 7:
Mendoza, Oscar; Bourdoncle, Anne; Boulé, Jean-Baptiste et al. (2016) G-quadruplexes and helicases. Nucleic Acids Res 44:1989-2006
Khan, Irfan; Sommers, Joshua A; Brosh Jr, Robert M (2015) Close encounters for the first time: Helicase interactions with DNA damage. DNA Repair (Amst) 33:43-59
Sommers, Joshua A; Suhasini, Avvaru N; Brosh Jr, Robert M (2015) Protein degradation pathways regulate the functions of helicases in the DNA damage response and maintenance of genomic stability. Biomolecules 5:590-616
Niu, Wenze; Zang, Tong; Smith, Derek K et al. (2015) SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Reports 4:780-94
Khan, Irfan; Suhasini, Avvaru N; Banerjee, Taraswi et al. (2014) Impact of age-associated cyclopurine lesions on DNA repair helicases. PLoS One 9:e113293
Bharti, Sanjay Kumar; Khan, Irfan; Banerjee, Taraswi et al. (2014) Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome. Cell Mol Life Sci 71:2625-39
Sommers, Joshua A; Banerjee, Taraswi; Hinds, Twila et al. (2014) Novel function of the Fanconi anemia group J or RECQ1 helicase to disrupt protein-DNA complexes in a replication protein A-stimulated manner. J Biol Chem 289:19928-41
Henderson, Alexander; Wu, Yuliang; Huang, Yu Chuan et al. (2014) Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res 42:860-9

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