SFB 1036:  Cellular Surveillance and Damage Response

• Subject Area: Biology
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 201348542

• Final Report Year: 2021

Final Report Abstract

A fundamental principle of life is the ability to maintain the functioning of biological systems in a changing environment. To achieve this, organisms have developed safeguarding mechanisms that monitor the integrity and functionality of their structures at all levels: from organs and tissues, cells, cellular organelles and subcellular compartments, to molecular machines and individual macromolecules. Cellular surveillance systems sense dysfunction or damage of individual components and elicit adaptive stress responses to ensure cellular or organismal survival by orchestrating their repair, removal and replacement. Failure or deregulation of these surveillance mechanisms is associated with aging and a plethora of diseases including cancer, neurodegeneration and inflammatory disorders. The CRC1036 was aiming at a molecular understanding of cellular stress response and surveillance pathways. In essence, this requires elucidation of how stress renders molecules, macromolecular assemblies and cellular processes damaged and dysfunctional, and how stress states and damage are sensed and signaled to elicit the appropriate response. Dozens of different quality control pathways exist within cells, making a comprehensive analysis challenging. We therefore established the CRC1036 consortium that allows to comparatively and synergistically investigate a spectrum of different strategic elements and mechanisms employed by stress responses and repair systems. In the two funding periods, we studied surveillance systems for DNA, RNA and proteins and the processes related to synthesis of these molecules (e.g. transcription and translation). This work generated new insights into fundamental principles at several levels, including new regulatory mechanisms that connect individual systems at the systemic level. We provided an in-depth analysis of selected stress sensing and signaling mechanisms as well as of damage repair and elimination mechanisms at the molecular and structural level, with major emphasis on protein quality control. Overall, the CRC is embedded in the environment of the Heidelberg/Mannheim life science campus, drawing expertise from seven participating basic biology and biomedical research centers (ZMBH, BZH, COS, DKFZ, EMBL, Medical Faculties Heidelberg and Mannheim). This broad structure of the consortium provided the basis for reaching major steps towards its long-term goal of gaining mechanistic understanding of cellular surveillance systems and damage response pathways.

Publications

• Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. PNAS (2013) 110, E4203-4212
  Bitomsky, N, Conrad, E, Moritz, C, Polonio-Vallon, T, Sombroek, D, Schultheiss, K, Glas, C, Greiner, V, Herbel, C, Mantovani, F, del Sal, G, Peri, F, Hofmann, TG
  (See online at https://doi.org/10.1073/pnas.1310001110)
• Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7. Mol Cell (2013) Nov 7;52(3):303-13
  Chen S, Seiler J, Santiago-Reichelt M, Felbel K, Grummt I, Voit R
  (See online at https://doi.org/10.1016/j.molcel.2013.10.010)
• Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell (2013) 153:869-81
  Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G
  (See online at https://doi.org/10.1016/j.cell.2013.04.016)
• High nutrient levels and TORC1 activity reduce cell viability following prolonged telomere dysfunction and cell cycle arrest. Cell Rep. (2014) 9, 324-335
  Klermund, J, Bender, K, Luke B
  (See online at https://doi.org/10.1016/j.celrep.2014.08.053)
• Protein quality control at the inner nuclear membrane. Nature (2014) 516, 410-413
  Khmelinskii, A, Blaszczak, E, Pantazopoulou, M, Fischer, B, Omnus, DJ, Le Dez, G, Brossard, A, Gunnarsson, A, Barry, JD, Meurer, M, Kirrmaier, D, Boone, C, Rabout, G, Ljungdahl, P, Knop, M
  (See online at https://doi.org/10.1038/nature14096)
• A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Blood (2015) 125(14):2265–75
  Guida C, Altamura S, Klein FA, Galy B, Boutros M, Ulmer AJ, Hentze MW, Muckenthaler MU
  (See online at https://doi.org/10.1182/blood-2014-08-595256)
• Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature (2015) 524, 247 – 251
  Nillegoda, N.B., Kirstein, J., Szlachcic, A., Berynskyy, M., Stank, A., Stengel, F., Arnsburg, K., Gao, X., Scior, A., Aebersold, R., Guilbride, D.L., Wade, R.C., Morimoto, R.I., Mayer, M.P., Bukau, B.
  (See online at https://doi.org/10.1038/nature14884)
• Downregulation of N-terminal acetylation triggers ABA-mediated drought responses in Arabidopsis. Nat Commun (2015) 6, 7640
  Linster, E., Stephan, I., Bienvenut, W.V., Maple-Grodem, J., Myklebust, L.M., Huber, M., Reichelt, M., Sticht, C., Geir Moller, S., Meinnel, T., Arnesen, T., Giglione, C., Hell, R., and Wirtz, M.
  (See online at https://doi.org/10.1038/ncomms8640)
• Intramembrane protease RHBDL4 cleaves oligosaccharyltransferase subunits to target them for ER-associated degradation. J. Cell Sci. (2016) Jun 16; 6:27342
  Knopf JD, Landscheidt N, Pegg CL, Schulz BL, Kühnle N, Wei CW, Huck S, Lemberg MK
  (See online at https://doi.org/10.1242/jcs.243790)
• Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1. eLife (2016) 5: e11576
  Hentze N, Le Breton L, Wiesner J, Kempf G, Mayer MP
  (See online at https://doi.org/10.7554/elife.11576)
• Realtime monitoring of basal H2O2 levels with peroxiredoxin-based probes. Nat Chem Biol (2016) 12:437-443
  Morgan B, Van Laer K, Owusu TN, Ezerina D, Pastor-Flores D, Amponsah PS, Tursch A, Dick TP
  (See online at https://doi.org/10.1038/nchembio.2067)
• Redox regulation of SUMO enzymes is required for ATM activity and survival in oxidative stress. EMBO J. (2016) 35:1312-1329
  Stankovic-Valentin, N., Drzewicka, K., König, C., Schiebel, E., Melchior, F.
  (See online at https://doi.org/10.15252/embj.201593404)
• The differential expression of alternatively polyadenylated transcripts is a common stressinduced response mechanism that modulates mammalian mRNA expression in a quantitative and qualitative fashion. RNA (2016) 22:1441-53
  Hollerer, I., Curk, T., Haase, B., Benes, V., Hauer, C., Neu-Yilik, G., Bhuvanagiri, M., Hentze, M.W., Kulozik, A.E.
  (See online at https://doi.org/10.1261/rna.055657.115)
• The Rqc2/Tae2 subunit of the ribosomeassociated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife (2016) Mar 4;5:e11794
  Yonashiro R, Tahara EB, Bengtson MH, Khokhrina M, Lorenz H, Chen KC, Kigoshi-Tansho Y, Savas JN, Yates JR, Kay SA, Craig EA, Mogk A, Bukau B, Joazeiro CA
  (See online at https://doi.org/10.7554/elife.11794)
• SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability. Genes Dev. (2017) Jul 1; 31(13):1370-1381
  Song C, Hotz-Wagenblatt A, Voit R, Grummt I
  (See online at https://doi.org/10.1101/gad.300624.117)
• Structural basis of HypK regulating N-terminal acetylation by the NatA complex, Nat Commun (2017) 8: 15726. 06
  Weyer, F.A., Gumiero, A., Lapouge, K., Bange, G., Kopp, J. & Sinning, I.
  (See online at https://doi.org/10.1038/ncomms15726)
• Sulfur availability regulates plant growth via glucose-TOR signaling. Nature Commun (2017) 8, 1174
  Dong, Y., Silbermann, M., Speiser, A., Forieri, I., Linster, E., Poschet, G., Allboje Samami, A., Wanatabe, M., Sticht, C., Teleman, A.A., Deragon, J.-M., Saito, K., Hell, R., and Wirtz, M.
  (See online at https://doi.org/10.1038/s41467-017-01224-w)
• Temporal and compartment-specific signals co-ordinate mitotic exit with spindle position. Nat. Comm. (2017) Jan 24:8:14129
  Caydasi, A.K., Khmelinskii, A., Duenas-Sanchez, R., Kurtulmus, B., Knop, M. and Pereira, G.
  (See online at https://doi.org/10.1038/ncomms14129)
• Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases. Nat Chem Biol (2017) 13, 709-714
  Lauinger, L., Li, J., Shostak, A., Cemel, I. A., Ha, N., Zhang, Y., Merkl, P. E., Obermeyer, S., Stankovic- Valentin, N., Schafmeier, T., Wever, W. J., Bowers, A. A., Carter, K. P., Palmer, A. E., Tschochner, H., Melchior, F., Deshaies, R. J., Brunner, M., and Diernfellner, A.
  (See online at https://doi.org/10.1038/nchembio.2370)
• Mapping degradation signals and pathways in a eukaryotic N-terminome. Mol Cell. (2018) 70:488-501.e5
  Kats, I., Khmelinskii, A., Kschonsak, M., Huber, F., Knieß, R.A., Bartosik, A., Knop, M.
  (See online at https://doi.org/10.1016/j.molcel.2018.03.033)
• (2019) A pathway linking translation stress to checkpoint kinase 2 signaling in Neurospora crassa. Proc Natl Acad Sci U S A (2019) 116, 17271-17279
  Diernfellner, A. C. R., Lauinger, L., Shostak, A., and Brunner, M.
  (See online at https://doi.org/10.1073/pnas.1815396116)
• Alanine Tails Signal Proteolysis in Bacterial Ribosome-Associated Quality Control. Cell (2019) Jun 27;178(1):76-90.e22
  Lytvynenko I, Paternoga H, Thrun A, Balke A, Müller TA, Chiang CH, Nagler K, Tsaprailis G, Anders S, Bischofs I, Maupin-Furlow JA, Spahn CMT, Joazeiro CAP
  (See online at https://doi.org/10.1016/j.cell.2019.05.002)
• Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis. Nature Commun. (2019) 10:4851
  Ho, C.-T., Grousl, T., Shatz, O., Jawed, A., Rutger-Herreros, C., Semmelink, M., Zahn, R., Richter, K., Bukau, B., Mogk, A.
  (See online at https://doi.org/10.1038/s41467-019-12868-1)
• Centromeric CENP-A loading requires accurate mitotic timing, which is linked to checkpoint proteins. PLoS Genet. (2019) Sep 25;15(9): e1008380
  Pauleau A, Kajtez J, Bergner A, Erhardt S
  (See online at https://doi.org/10.1371/journal.pgen.1008380)
• Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins. eLife (2019) June 7; 8:e45506
  Dederer V, Khmelinskii A, Huhn A, Okreglak V, Knop M, Lemberg MK
  (See online at https://doi.org/10.7554/elife.45506)
• Localization of Drosophila CENP-A to non-centromeric sites depends on the NuRD complex. Nucleic Acids Res. (2019)
  Demerdizen E, Spiller-Becker M, Förtsch A, Wilhelm A, Bergner A, Bade D, Hessling B, Erhardt S
  (See online at https://doi.org/10.1093/nar/gkz962)
• TIAR marks nuclear G2/M transition granules and restricts CDK1 activity under replication stress. EMBO Rep (2019) 20: e46224
  Lafarga V, Sung HM, Haneke K, Roessig L, Pauleau AL, Bruer M, Rodriguez-Acebes S, Lopez-Contreras AJ, Gruss OJ, Erhardt S, Mendez J, Fernandez-Capetillo O, Stoecklin G
  (See online at https://doi.org/10.15252/embr.201846224)
• Translational Regulation of Pmt1 and Pmt2 by Bfr1 Affects Unfolded Protein O- Mannosylation. Int J Mol Sci. (2019) 20(24):6220
  Castells-Ballester J, Rinis N, Kotan I, Gal L, Bausewein D, Kats I, Zatorska E, Kramer G, Bukau B, Schuldiner M, Strahl S
  (See online at https://doi.org/10.3390/ijms20246220)
• A role for annexin A2 in scaffolding the peroxiredoxin 2-STAT3 redox relay complex. Nat Commun (2020) 11:4512
  Talwar D, Messens J, Dick TP
  (See online at https://doi.org/10.1038/s41467-020-18324-9)
• Cdk4 and Cdk6 couple the cell cycle machinery to cell growth via mTORC1. Cell Reports (2020) 31:107504
  Romero-Pozuelo J, Figlia G, Kaya O, Martin-Villalba A and Teleman AA
  (See online at https://doi.org/10.1016/j.celrep.2020.03.068)
• Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70- mediated trimer unzipping and dissociation from DNA. The EMBO J (2020) 39: e104096
  Kmiecik SW, Le Breton L, Mayer MP
  (See online at https://doi.org/10.15252/embj.2019104096)
• Functional implications of MIR domains in protein O- mannosylation. Elife (2020) 9:e61189
  Chiapparino A, Grbavac A, Jonker HR, Hackmann Y, Mortensen S, Zatorska E, Schott A, Stier G, Saxena K, Wild K, Schwalbe H, Strahl S, Sinning I
  (See online at https://doi.org/10.7554/elife.61189)
• Molecular dissection of amyloid disaggregation by the human Hsp70 chaperone. Nature (2020), 587: 483–488
  Wentink, A.S., Nillegoda, N.B., Feufel, J., Ubartaitė, G., Schneider, C.P., De Los Rios, P., Hennig, J., Barducci, A., Bukau, B
  (See online at https://doi.org/10.1038/s41586-020-2904-6)
• Reducing Insulin/IGF1 Signaling Protects Against Non-Cell Autonomous Vesicle Rupture Caused by SNCA Spreading. Autophagy (2020) 16(5):878-899
  Sandhof CA, Hoppe SO, Druffel-Augustin S, Gallrein C, Kirstein J, Voisine C, Nussbaum-Krammer C
  (See online at https://doi.org/10.1080/15548627.2019.1643657)
• Selective 40S footprinting reveals captethered ribosome scanning in human cells. Mol Cell (2020) 79:561-574.e5
  Bohlen J, Fenzl K, Kramer G, Bukau B and Teleman AA
  (See online at https://doi.org/10.1016/j.molcel.2020.06.005)
• The HSP110/HSP70 disaggregation system generates spreading-competent toxic αsynuclein species. EMBO J (2020) Mai 25:e103954
  Tittelmeier J, Sandhof CA, Ries HM, Druffel-Augustin S, Klemmer A, Mogk A, Bukau B, Nussbaum- Krammer C
  (See online at https://doi.org/10.15252/embj.2019103954)
• The ribosome-associated complex RAC serves in a relay that directs nascent chains to Ssb. Nat Commun (2020) 11: 1504
  Zhang, Y., Valentín Gesé, G., Conz, C., Lapouge, L., Kopp, J., Wölfle, T., Rospert, S. & Sinning, I.
  (See online at https://doi.org/10.1038/s41467-020-15313-w)
• Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing. Mol Cell. (2021) Mar 22:S1097-2765(21)00172-6
  Thrun A, Garzia A, Kigoshi-Tansho Y, Patil PR, Umbaugh CS, Dallinger T, Liu J, Kreger S, Patrizi A, Cox GA, Tuschl T, Joazeiro CAP
  (See online at https://doi.org/10.1016/j.molcel.2021.03.004)
• Liver sinusoidal endothelial cells suppress BMP2 production in response to TGFβ pathway activation. Hepatology. (2021) May 13
  Colucci S, Altamura S, Marques O, Dropmann A, Horvat NK, Müdder K, Hammad S, Dooley S, Muckenthaler MU
  (See online at https://doi.org/10.1002/hep.31900)
• Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase. Mol Cell (2021)
  Kong KYE, Fischer B, Meurer M, Kats I, Li Z, Rühle F, Barry JD, Kirrmaier D, Chevyreva V, San Luis BJ, Costanzo M, Huber W, Andrews BJ, Boone C, Knop M, Khmelinskii A
  (See online at https://doi.org/10.1016/j.molcel.2021.04.018)