GOODARZI, AARON - University of Calgary - Department of Biochemistry & Molecular Biology

个人简介

B.Sc. (Bachelor of Science) Ph.D. (Doctor of Philosophy)

研究领域

The technological age has seen humans increasingly exposed to sources of DNA-damaging radiation. A double-edged sword, radiation has enabled great advances in energy production, medical diagnosis and cancer therapy while simultaneously increasing our risk of nuclear accident or attack. The most deleterious lesion caused by radiation is a break in both strands of our DNA, a DNA double-strand break. Unless accurately repaired by the molecular machinery of our cells, DNA double-strand breaks can lead to genome instability - a fundamental driver of cancer and accelerated ageing. Human DNA is naturally packaged around small protein complexes made up of histones, subdividing our DNA into manageable units called ‘nucleosomes'. Collectively, this complex of DNA and protein is referred to as ‘chromatin'. Mammalian chromatin exists within a gradient of comparably relaxed and accessible euchromatin to highly condensed and inaccessible heterochromatin - a distribution underlying the hugely increased size and complexity of our genome relative to our distant evolutionary ancestors. We now know that DNA double-strand breaks occurring within regions of densely packaged and complex chromatin (heterochromatin) are much more difficult to repair compared to breaks occurring in open chromatin, requiring substantially longer to resolve following radiation exposure. Numerous additional molecular events need to occur in flawless succession to achieve the repair of a heterochromatic DNA double strand break. Among these events is the manipulation of the local nucleosome arrangement around the DNA double-strand break by so-called ‘nucleosome remodeling' enzymes. My research endeavors to understand how processes involving nucleosome remodeling enzymes underlie DNA double-strand break repair in complex chromatin and, in doing so, improve our knowledge of cancer formation, human ageing and radiation protection.

近期论文

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Hansen RK, Mund A, Poulsen SL, Sandoval M, Klement K, Tsouroula K, Tollenaere MA, Räschle M, Soria R, Offermanns S, Worzfeld T, Grosse R, Brandt DT, Rozell B, Mann M, Cole F, Soutoglou E*,Goodarzi AA*, Daniel JA*, Mailand N*, Bekker-Jensen S*. SCAI promotes DNA double-strand break repair in distinct chromosomal contexts. Nature Cell Biology. 2016. Dec;18(12):1357-1366. Klement K, Luijsterburg MS, Pinder JB, Cena CS, Del Nero V, Wintersinger CM, Dellaire G, van Attikum H, Goodarzi AA. Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair. Journal of Cell Biology. 2014; 207(6):717-33. Kakarougkas A, Ismail A, Klement K, Goodarzi AA, Lobrich M, Conrad S, Freire R, Shibata A, Lobrich M, Jeggo PA. Opposing roles for 53BP1 during homologous recombination. Nucleic Acids Research. 2013. 41(21):9719-31. Lee D-H, Goodarzi AA, Adelmant GO, Pan Y, Marto JA, Jeggo PA, Chowdhury D. Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response. EMBO Journal. 2012 31(10):2403-15. Goodarzi AA, Kurka T, Jeggo PA. KAP-1 phosphorylation regulates heterochromatic CHD3 nucleosome remodeling during the DNA double strand break response. Nature Struct. Mol. Biol. 2011 18(7):831-9. Brunton H, Goodarzi AA, Noon AT, Shrikhande A, Hansen RS, Jeggo PA and Shibata A. Analysis of human syndromes with disordered chromatin reveals the impact of heterochromatin on the efficacy of ATM-dependent G2/M checkpoint arrest. Mol. Cell. Biol. 2011 31(19):4022-35. Woodbine L, Brunton H, Goodarzi AA, Shibata A, Jeggo PA. Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. Nucleic Acids Res. 2011 Sep 1;39(16):6986-97. Shibata A, Barton O, Noon AT, Dahm K, Deckbar D, Goodarzi AA, Löbrich M, Jeggo PA. The role of ATM and the damage response mediator proteins, 53BP1 and MDC1, in the maintenance of G2/M checkpoint arrest. Mol. Cell. Biol. 2010. 30(13):3371-83. Noon AT, Shibata A, Rief N, Löbrich M, Stewart GS, Jeggo PA, Goodarzi AA. 53BP1 facilitates heterochromatic DNA double strand break repair by enabling highly localized KAP-1 phosphorylation. Nature Cell Biology 2010 Feb;12(2):177-84. Lee J-H, Goodarzi AA, Jeggo PA, Paull T. 53BP1 promotes ATM activity through direct interactions with the MRN complex. EMBO Journal. 2010 Feb 3;29(3):574-85. Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Rief N, Goodarzi AA, Krempler A, Jeggo PA and Löbrich M. A role for ATM and Artemis in homologous recombination repair of radiation-induced DNA double strand breaks. EMBO Journal. 2009 Nov 4;28(21):3413-27. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Molecular Cell. 2008 31(2):167-77. (Cited by F1000) Commented in: Fernandez-Capetillo O, Nussenzweig A. ATM breaks into heterochromatin. Molecular Cell. 2008 Aug 8;31(3):303-4. Review Articles (selected) - Click here for a complete list Klement K, Goodarzi AA. DNA double strand break responses and chromatin alterations within the aging cell. Exp. Cell. Res. 2014. In press. Review. Moore S, Stanley FK, Goodarzi AA. The repair of DNA double strand breaks caused by high linear energy transfer irradiation - no simple task. DNA Repair. 2014. 17:64-73. Review. Stanley FK, Moore S, Goodarzi AA. CHD chromatin remodelling enzymes and the DNA double strand break response. Mutation Research. 2013. 750(1-2):31-44. Review. Goodarzi AA, Jeggo PA. The repair and signaling responses to DNA double-strand breaks.Advances in Genetics. 2013; 82:1-45. Review. Goodarzi AA, Jeggo PA. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. International Journal of Molecular Sciences. 2012 Sept; 13(9), 11844-11860. Review. Goodarzi AA, Jeggo PA. Irradiation induced foci (IRIF) as a biomarker for radiosensitivity and radiation exposure. Mutation Research. 2012 Aug 1;736(1-2):39-47. Review. Noon AT and Goodarzi AA. 53BP1-mediated DNA double strand break repair: insert bad pun here. DNA Repair. 2011 Oct 10;10(10):1071-1076. ‘Hot Topics’ Review. Goodarzi AA, Löbrich M, Jeggo PA. The influence of heterochromatin on DNA double strand break (DSB) repair: Getting the strong, silent type to relax. DNA Repair 2010. 9(12):1273-82. Löbrich M, Shibata A, Beucher A, Fisher A, Ensminger M, Goodarzi AA, Barton O, Jeggo PA. γH2AX foci analysis for monitoring DNA double-strand break repair: Strengths, limitations and optimization Cell Cycle 2010. Feb 15;9:4, 1-8; Review.