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Helicases and Genomic Integrity Section

Robert M. Brosh, Jr, Ph.D., Chief

The Helicases and Genomic Integrity Section investigates the roles of human DNA helicases in genomic stability, prompted by the discovery of hereditary helicase disorders characterized by accelerated aging. Dr. Brosh’s group has made important contributions to deciphering molecular mechanisms whereby human DNA helicases preserve chromosomal stability and cellular homeostasis. The DNA Helicase Section was the first to discover a small molecule inhibitor of the WRN helicase, defective in the premature aging disease Werner syndrome. Use of small molecules to target human helicases for inhibition (or activation) in a cell-based model system is a novel approach to assign specific helicase functions in vivo and may pave the way for development of therapeutic strategies. The Helicases and Genomic Integrity Section has provided fresh insights into the biochemical and cellular functions of several human DNA helicases, including RECQL1 that is implicated in the replication stress response and represents a potential anti-cancer therapy target. They also study FANCJ helicase which is genetically linked to the bone marrow failure disorder Fanconi Anemia. The team studies mitochondrial DNA metabolism involving Twinkle helicase and G-quadruplex associated genetic variations. Research of the Helicases and Genomic Integrity Section using various model systems has provided a new understanding of helicase pathways to prevent or correct genomic DNA damage, a causative force for cellular senescence and organismal decline associated with aging.

Portfolio/Research Areas

  • helicase
  • DNA repair
  • replication
  • recombination
  • genomic stability
  • DNA metabolism
  • premature aging
  • chromosomal integrity
  • G-quadruplex, mutation
  • DNA damage, senescence
  • replication stress response
  • mitochondrial DNA metabolism
  • Werner syndrome
  • Bloom’s syndrome
  • Warsaw Breakage Syndrome
  • Fanconi Anemia
  • genetic disease
  • cancer
  • age-related phenotypes
  • small molecule
  • RecQ helicase
  • Fe-S helicase
  • Twinkle helicase

Findings and Publications

Butler TJ, Estep KN, Sommers JA, Maul RW, Moore AZ, Bandinelli S, Cucca F, Tuke MA, Wood AR, Bharti SK, Bogenhagen DF, Yakubovskaya E, Garcia-Diaz M, Guilliam TA, Byrd AK, Raney KD, Doherty AJ, Ferrucci L, Schlessinger D, Ding J, Brosh RM Jr., Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro. Hum Mol Genet (2020) 29: 1292-1309.

Banerjee T, Bharti SK, Sommers JA, Awate S, Bellani MA, Khan I, Bradley L, King GA, Seol Y, Vidhyasagar V, Wu Y, Abe T, Kobayashi K, Shin-Ya K, Kitao H, Wold MS, Branzei D, Neuman KC, Brosh RM Jr., A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair. strand separation by RECQ1 is required for RPA-mediated response to replication stress. Nucleic Acid Res (2018) 46: 6238-56.

Brosh, RM Jr., DNA helicases involved in DNA repair and their roles in cancer.  Nat Rev Cancer (2013) 13: 542-58.

Suhasini AN, Rawtani NA, Wu Y, Sommers JA, Sharma S, Mosedale G, North PS, Cantor SB, Hickson ID, Brosh RM Jr., Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom’s syndrome.  EMBO J (2011) 30: 692-705.

Aggarwal M, Sommers JA, Shoemaker RH, Brosh RM Jr., Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress.  Proc Natl Acad Sci USA (2011) 108: 1525-30.

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