Andreas Brachner

Publications (9) View all

• Article: The endonuclease Ankle1 requires its LEM and GIY-YIG motifs for DNA cleavage in vivo.

  Andreas Brachner, Juliane Braun, Medini Ghodgaonkar, Dennis Castor, Livija Zlopasa, Veronika Ehrlich, Josef Jiricny, Josef Gotzmann, Siegfried Knasmüller, Roland Foisner
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  ABSTRACT: The LEM domain (for lamina-associated polypeptide, emerin, MAN1 domain) defines a group of nuclear proteins that bind chromatin through interaction of the LEM motif with the conserved DNA crosslinking protein, barrier-to-autointegration factor (BAF). Here, we describe a LEM protein annotated in databases as 'Ankyrin repeat and LEM domain-containing protein 1' (Ankle1). We show that Ankle1 is conserved in metazoans and contains a unique C-terminal GIY-YIG motif that confers endonuclease activity in vitro and in vivo. In mammals, Ankle1 is predominantly expressed in hematopoietic tissues. Although most characterized LEM proteins are components of the inner nuclear membrane, ectopic Ankle1 shuttles between cytoplasm and nucleus. Ankle1 enriched in the nucleoplasm induces DNA cleavage and DNA damage response. This activity requires both the catalytic C-terminal GIY-YIG domain and the LEM motif, which binds chromatin via BAF. Hence, Ankle1 is an unusual LEM protein with a GIY-YIG-type endonuclease activity in higher eukaryotes.
  Journal of Cell Science 03/2012; 125(Pt 4):1048-57. · 6.11 Impact Factor
• Article: Evolvement of LEM proteins as chromatin tethers at the nuclear periphery.

  Andreas Brachner, Roland Foisner
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  ABSTRACT: The nuclear envelope in eukaryotic cells has important roles in chromatin organization. The inner nuclear membrane contains over 60 transmembrane proteins. LEM [LAP2 (lamina-associated polypeptide 2)/emerin/MAN1] domain-containing proteins of the inner nuclear membrane are involved in tethering chromatin to the nuclear envelope and affect gene expression. They contain a common structural, bihelical motif, the so-called LEM domain, which mediates binding to a conserved chromatin protein, BAF (barrier to autointegration factor). Interestingly, this domain is highly related to other bihelical motifs, termed HeH (helix-extension-helix) and SAP {SAF (scaffold attachment factor)/acinus/PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)]} motifs, which are directly linked to DNA. In the present paper, we summarize evidence that the LEM motif evolved from the HeH and SAP domains concomitantly with BAF. In addition, we discuss the potential evolution of HeH/SAP and LEM domain-containing proteins and their role in chromatin tethering and gene regulation from unicellular eukaryotes to mammals.
  Biochemical Society Transactions 12/2011; 39(6):1735-41. · 3.71 Impact Factor
• Article: Lamins reach out to novel functions in DNA damage repair.

  Andreas Brachner, Roland Foisner
  Cell cycle (Georgetown, Tex.) 10/2011; 10(20):3426. · 5.36 Impact Factor
• Article: Molecular mechanisms of centrosome and cytoskeleton anchorage at the nuclear envelope.

  Maria Schneider, Wenshu Lu, Sascha Neumann, Andreas Brachner, Josef Gotzmann, Angelika A Noegel, Iakowos Karakesisoglou
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  ABSTRACT: Cell polarization is a fundamental process underpinning organismal development, and tissue homeostasis, which requires an orchestrated interplay of nuclear, cytoskeletal, and centrosomal structures. The underlying molecular mechanisms, however, still remain elusive. Here we report that kinesin-1/nesprin-2/SUN-domain macromolecular assemblies, spanning the entire nuclear envelope (NE), function in cell polarization by anchoring cytoskeletal structures to the nuclear lamina. Nesprin-2 forms complexes with the kinesin-1 motor protein apparatus by associating with and recruiting kinesin light chain 1 (KLC1) to the outer nuclear membrane. Similar to nesprin-2, KLC1 requires lamin A/C for proper NE localization. The depletion of nesprin-2 or KLC1, or the uncoupling of nesprin-2/SUN-domain protein associations impairs cell polarization during wounding and dislodges the centrosome from the NE. In addition nesprin-2 loss has profound effects on KLC1 levels, the cytoskeleton, and Golgi apparatus organization. Collectively these data show that NE-associated proteins are pivotal determinants of cell architecture and polarization.
  Cellular and Molecular Life Sciences CMLS 10/2010; 68(9):1593-610. · 6.57 Impact Factor
• Article: NORE1B is a putative tumor suppressor in hepatocarcinogenesis and may act via RASSF1A.

  Doris Macheiner, Christine Gauglhofer, Chantal Rodgarkia-Dara, Michael Grusch, Andreas Brachner, Christoph Bichler, Daniela Kandioler, Hedwig Sutterlüty, Wolfgang Mikulits, Rolf Schulte-Hermann, Bettina Grasl-Kraupp
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  ABSTRACT: Recently, we found epigenetic silencing of the Ras effector genes NORE1B and/or RASSF1A in 97% of the hepatocellular carcinoma (HCC) investigated. This is strong evidence that the two genes are of major significance in hepatocarcinogenesis. Although RASSF1A serves as a tumor suppressor gene, the functions of NORE1B are largely unknown. Here, we studied the role of NORE1B for growth and transformation of cells. To understand the molecular mechanisms of action of the gene, we used the wild-type form and deletion mutants without the NH(2) terminus and CENTRAL domain, the Ras association (RA) domain, or the COOH-terminal SARAH-domain. Intact RA and SARAH-domains were found to be necessary for NORE1B (a) to increase the G(0)-G(1) fraction in hepatoma cells, (b) to suppress c-Myc/Ha-Ras-induced cell transformation, and (c) to interact closely with RASSF1A, as determined with fluorescence resonance energy transfer. In further studies, cell cycle delay by NORE1B was equally effective in hepatocyte cell lines with wild-type or mutant Ras suggesting that NORE1B does not interact with either Ras. In conclusion, NORE1B suppresses replication and transformation of cells as effectively as RASSF1A and thus is a putative tumor suppressor gene. NORE1B interacts physically with RASSF1A and functional loss of one of the interacting partners may lead to uncontrolled growth and transformation of hepatocytes. This may explain the frequent epigenetic silencing of NORE1B and/or RASSF1A in HCC.
  Cancer Research 02/2009; 69(1):235-42. · 7.86 Impact Factor