Research units - Molecular Genetics

Molecular Genetics

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Proper repair of spontaneous and environmentally induced DNA damage is crucial for normal human development and prevention of cancer and premature ageing. The laboratory is interested in molecular mechanisms involved in DNA damage signaling and repair, and we are using a wide range of biochemical, cell biological, molecular biology, structural and genetic approaches in mammalian and yeast cells for our studies.

Research Overview

We are interested in the role of protein-protein interactions in the DNA damage response, and how these are regulated by post-translational protein modification, particularly protein phosphorylation.  Key areas include the functional analysis of dense clusters of phosphorylation for ATM-like kinases (SQ/TQ cluster domains) and corresponding phosphopeptide-binding domains (FHAs, BRCTs etc).  We are studying proteins with these motifs (Chk2, Rad53, ASCIZ, Mdt1, Esl1/2) in yeast and mammalian cell systems.  We are also studying DNA damage-independent roles of these proteins in organ development, particularly the role of the Zinc-finger protein ASCIZ as a key regulator or early lung development.

Research Themes

Function and regulation of CHK2-like checkpoint kinases

DNA damage responses in budding yeast

Roles of ASCIZ in DNA repair

Roles of ASCIZ in organ development

Honours and PhD Projects

Role of a novel transcription factor in the regulation of early lung development

Role of ASCIZ in the DNA damage response and cancer development

Regulation of cell cycle checkpoint kinases

Staff

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A/Prof Jörg Heierhorst
Dr Lindus Conlan
Kimberly Gleeson
Nicolas Hoch
Sabine Jurado
Xianning Lai
Nora Tenis

Publication Highlights

    1. Heierhorst J, Kobe B, Feil SC, Parker MW, Benian GM, Weiss KR & Kemp BE (1996). Ca2+/S100 regulation of giant protein kinases. Nature 380, 636-39.
    2. Du X-J, Cole TC, Gao X-M, Tenis N, Köntgen F, Kemp BE & Heierhorst J (2002). Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice. Mol. Cell. Biol. 22, 2821-2829.
    3. Pike BL, Yongkiettrakul S, Tsai M-D & Heierhorst J (2003). Diverse but overlapping functions of the two forkhead-associated (FHA) domains in Rad53 checkpoint kinase activation. J. Biol. Chem. 278, 30421-30424.
    4. McNees CJ, Conlan LA, Tenis N & Heierhorst J (2005). ASCIZ regulates lesion-specific RAD51 focus formation and apoptosis after methylating DNA damage. EMBO J. 24, 2447-2457.
    5. Traven A & Heierhorst J (2005). SQ/TQ cluster domains: concentrated ATM/ATR kinase phosphorylation site regions in DNA damage response proteins. BioEssays 27, 397-407.
    6. Pike BL & Heierhorst J (2007). Mdt1 facilitates efficient repair of blocked DNA double-strand breaks and recombinational maintenance of telomeres. Mol. Cell. Biol. 27, 6532-6545.
    7. Hammet A, Magill C, Heierhorst J & Jackson SP (2007). Rad9 BRCT domains interact with phosphorylated H2AX to regulate the G1 checkpoint in budding yeast. EMBO Rep. 8, 851-857.
    8. Lee H, Yuan C, Hammet A, Mahajan A, Wu MR, Chen ESW, Su MI, Heierhorst J* & Tsai MD (2008). Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade. Mol. Cell 30, 767-778. (*co-senior author)
    9. Jurado S, Smyth I, Van Denderen B, Tenis N, Hammet A, Hewiitt K, Ng JL, McNees CJ, Kozlov SV, Oka H, Kobayashi M, Conlan LA, Cole TC, Yamamoto K, Taniguchi Y, Takeda S, Lavin MF & Heierhorst J (2010).  Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis.  PLoS Genetics 6, e1001170.
    10. Jurado S, Conlan LA, Baker EK, Ng JL, Tenis N, Hoch NC, Gleeson K, Smeets M, Izon D & Heierhorst J (2012).  Atm substrate chk2-interacting Zn2+-finger (ASCIZ) is a bi-functional transcriptional activator and feedback sensor of dynein light chain (DYNLL1) expression.  J. Biol. Chem.  287, in press. [http://www.jbc.org/cgi/doi/10.1074/jbc.M111.306019]