Using an approach known as RNA interference, we have specifically depleted human cells of the FANCJ DNA helicase and characterized the sensitivity of the cells to a small molecule compound that stabilizes G-quadruplex DNA structures. This work enabled us to elucidate a novel function of the FANCJ helicase in the manintenace of chromosomal stability. Since individuals carrying homozygous mutations in the FANCJ helicase gene have a genetic disorder known as Fanconi Anemia characterized by genomic instability and cancer, we believe our results shed new insights to the cellular pathways of FANCJ that serve to counter replciational stress due to alterante DNA structures such as G-quadruplexes that arise in vivo. We have used isogenic pairs of mutant and corrected chicken DT40 cells as well as human cells for genetic complementation studies. The mutant cell lines were used for structure-function studies of patient derived helicase-inactivating mutations. This work enabled us to define genotype-phenotype relationships between clinically relevant mutations and human genetic diseases. Another aspect of this work was to used genetically defined cancer and normal cell lines and small molecules to probed the molecualr and cellular functions of the Werner syndrome helicase. These efforts enabled us to determine that inhibition of WRN helicase activity inhibits cell proliferation and its DNA repair function in vivo. These efforts in the basic sciences help to advance the idea that DNA repair proteins may be targeted in anti-cancer therapy to increase the sensitivity of tumors to DNA damaging chemotherapy drugs or radiation. We have also employed yeast as a model genetic system to study the role of the Werner syndrome helicase in DNA replciation and repair. This work has enabled us to characterize the catalytic requirements of WRN in a defined genetic DNA repair pathway that operates to provide cellular resistance to alkylating agents which impose replicational stress. Lastly, we have utilized mouse as a model genetic system to characterize the role of a helicase ortholog (RECQ1) found in humans whose biological significance is not well understood. Characterization of th eprimary mouse embryonic fibroblasts from RECQ1 knockout mice has revealed that the RECQ1 helicase has unique and important roles in genomic stability maintenance.

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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
Henderson, Alexander; Wu, Yuliang; Huang, Yu Chuan et al. (2014) Detection of G-quadruplex DNA in mammalian cells. Nucleic Acids Res 42:860-9
Capo-Chichi, José-Mario; Bharti, Sanjay Kumar; Sommers, Joshua A et al. (2013) Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum Mutat 34:103-7
Suhasini, Avvaru N; Brosh Jr, Robert M (2013) DNA helicases associated with genetic instability, cancer, and aging. Adv Exp Med Biol 767:123-44
Brosh Jr, Robert M (2013) DNA helicases involved in DNA repair and their roles in cancer. Nat Rev Cancer 13:542-58
Suhasini, Avvaru N; Brosh Jr, Robert M (2013) Disease-causing missense mutations in human DNA helicase disorders. Mutat Res 752:138-52
Banerjee, Taraswi; Aggarwal, Monika; Brosh Jr, Robert M (2013) A new development in DNA repair modulation: discovery of a BLM helicase inhibitor. Cell Cycle 12:713-4
Bharti, Sanjay Kumar; Sommers, Joshua A; George, Fourbears et al. (2013) Specialization Among Iron-Sulfur Cluster Helicases to Resolve G-Quadruplex DNA Structures that Threaten Genomic Stability. J Biol Chem :
Suhasini, Avvaru N; Sommers, Joshua A; Muniandy, Parameswary A et al. (2013) Fanconi anemia group J helicase and MRE11 nuclease interact to facilitate the DNA damage response. Mol Cell Biol 33:2212-27
Aggarwal, Monika; Banerjee, Taraswi; Sommers, Joshua A et al. (2013) Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional fanconi anemia pathway. Cancer Res 73:5497-507

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