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SQSTM1/P62 Mediates Crosstalk Between Autophagy and the UPS in DNA Repair

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SQSTM1/P62 Mediates Crosstalk Between Autophagy and the UPS in DNA Repair Hewitt, G. , Carroll, B., Sarallah, R., Correia-Melo, C., Ogrodnik, M., Nelson, G., Otten, E. G., Manni, D., Antrobus, R., Morgan, B. A., von Zglinicki, T., Jurk, D., Seluanov, A., Gorbunova, V., Johansen, T., Passos, J. F., & Korolchuk, V. I. (2016). SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy, 12(10), 1917-1930. https://doi.org/10.1080/15548627.2016.1210368 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1080/15548627.2016.1210368 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Taylor & Francis at DOI: 10.1080/15548627.2016.1210368. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Autophagy ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: https://www.tandfonline.com/loi/kaup20 SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair Graeme Hewitt, Bernadette Carroll, Rezazadeh Sarallah, Clara Correia-Melo, Mikołaj Ogrodnik, Glyn Nelson, Elsje G. Otten, Diego Manni, Robin Antrobus, Brian A. Morgan, Thomas von Zglinicki, Diana Jurk, Andrei Seluanov, Vera Gorbunova, Terje Johansen, João F. Passos & Viktor I. Korolchuk To cite this article: Graeme Hewitt, Bernadette Carroll, Rezazadeh Sarallah, Clara Correia-Melo, Mikołaj Ogrodnik, Glyn Nelson, Elsje G. Otten, Diego Manni, Robin Antrobus, Brian A. Morgan, Thomas von Zglinicki, Diana Jurk, Andrei Seluanov, Vera Gorbunova, Terje Johansen, João F. Passos & Viktor I. Korolchuk (2016) SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair, Autophagy, 12:10, 1917-1930, DOI: 10.1080/15548627.2016.1210368 To link to this article: https://doi.org/10.1080/15548627.2016.1210368 © 2016 The Author(s). Published with View supplementary material license by Taylor & Francis Group, LLC© 2016 Graeme Hewitt, Bernadette Carroll, Rezazadeh Sarallah, Clara Correia-Melo, Mikołaj Ogrodnik, Glyn Nelson, Elsje G. Otten, Diego Manni, Robin Antrobus, Brian A. Morgan, Thomas von Zglinicki, Diana Jurk, Andrei Seluanov, Vera Gorbunova, Terje Johansen, João F. Passos, and Viktor I. Korolchuk. Accepted author version posted online: 08 Submit your article to this journal Jul 2016. Published online: 23 Aug 2016. Article views: 3044 View Crossmark data Citing articles: 21 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=kaup20 AUTOPHAGY 2016, VOL. 12, NO. 10, 1917–1930 http://dx.doi.org/10.1080/15548627.2016.1210368 BASIC RESEARCH PAPER SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair Graeme Hewitta, Bernadette Carrolla, Rezazadeh Sarallahc, Clara Correia-Meloa, Miko»aj Ogrodnika, Glyn Nelsona, Elsje G. Ottena, Diego Mannia, Robin Antrobusb, Brian A. Morgana, Thomas von Zglinickia, Diana Jurka, Andrei Seluanovc, Vera Gorbunovac, Terje Johansend,Jo~ao F. Passosa, and Viktor I. Korolchuka aInstitute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK; bCambridge Institute for Medical Research, Cambridge University, Cambridge, UK; cDepartment of Biology, University of Rochester, Rochester, NY USA; dMolecular Cancer Research Group, Department of Medical Biology, University of Tromsø – The Arctic University of Norway, Tromsø, Norway ABSTRACT ARTICLE HISTORY SQSTM1/p62 (sequestosome 1) selectively targets polyubiquitinated proteins for degradation via Received 9 September 2015 macroautophagy and the proteasome. Additionally, SQSTM1 shuttles between the cytoplasmic and nuclear Revised 7 June 2016 compartments, although its role in the nucleus is relatively unknown. Here, we report that SQSTM1 Accepted 27 June 2016 dynamically associates with DNA damage foci (DDF) and regulates DNA repair. Upon induction of DNA KEYWORDS damage SQSTM1 interacts with FLNA (filamin A), which has previously been shown to recruit DNA repair aging; autophagy; DNA protein RAD51 (RAD51 recombinase) to double-strand breaks and facilitate homologous recombination damage; homologous (HR). SQSTM1 promotes proteasomal degradation of FLNA and RAD51 within the nucleus, resulting in recombination; reduced levels of nuclear RAD51 and slower DNA repair. SQSTM1 regulates the ratio between HR and nonhomologous end joining; nonhomologous end joining (NHEJ) by promoting the latter at the expense of the former. This SQSTM1- SQSTM1 dependent mechanism mediates the effect of macroautophagy on DNA repair. Moreover, nuclear localization of SQSTM1 and its association with DDF increase with aging and are prevented by life-span- extending dietary restriction, suggesting that an imbalance in the mechanism identified here may contribute to aging and age-related diseases. Introduction on DNA repair may be achieved by the transport of specific The DNA damage response (DDR) is essential for the mainte- nuclear proteins into the cytoplasm where they are recruited nance of genome stability and its impairment is implicated in for autophagic degradation. Specifically, it has been suggested human diseases and aging.1,2 The role of the ubiquitin-protea- that acetylation-dependent autophagic turnover of the recom- some system (UPS) in the control of DDR pathways is well bination protein Sae2 promotes DNA repair in yeast6 although established.3 Proteasomal degradation plays the key role in the this mechanism has recently been challenged in mammalian turnover of the components of the DNA repair machinery dur- cells; turnover of CHEK1 (checkpoint kinase 1) via either auto- ing genome maintenance and promotes efficient resolution of phagy or CMA has been proposed to mediate the positive role DNA damage foci (DDF), thus allowing cell cycle progression. of these degradative pathways in DDR.4,9 However, while the Recently, lysosome-dependent degradation pathways, including latter mechanism helps to explain how autophagy could affect macroautophagy (hereinafter autophagy) and chaperone-medi- signaling downstream of DDF the mechanisms allowing auto- ated autophagy (CMA) have also been demonstrated to affect phagy to promote DNA repair remain poorly understood. Dif- the DDR in eukaryotic cells. Specifically, suppression of auto- ferent mechanisms of double-strand DNA damage repair are phagy results in an aberrant DDR with delayed kinetics of controlled by dedicated molecular machinery and RAD51 and DNA repair and increased dependence on NHEJ at the expense TP53BP1 (tumor protein p53 binding protein 1) have been of HR.4-6 shown to promote HR and NHEJ, respectively. A differential Autophagy is thought to take place exclusively in the cyto- effect of autophagy on HR and NHEJ raises a possibility that plasm while DDR is a primarily nuclear process. Several mech- autophagy has a direct or an indirect effect on the levels or anisms have been proposed as a link between these 2 pathways. activity of these proteins.10 In some specific physiological contexts, such as deep cellular In eukaryotic cells activity of autophagy and UPS are senescence, transport of DDF from the nucleus into the cyto- tightly regulated and coordinated. Thus, impairment of pro- plasm followed by engulfment by autophagic membranes has teasomal degradation can be compensated by upregulation been observed.7,8 Alternatively, the positive effect of autophagy of autophagy, whereas inhibition of autophagy has been CONTACT Jo~ao F. Passos [email protected]; Viktor I. Korolchuk [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kaup. Supplemental data for this article can be accessed on the publisher’s website. © 2016 Graeme Hewitt, Bernadette Carroll, Rezazadeh Sarallah, Clara Correia-Melo, Miko»aj Ogrodnik, Glyn Nelson, Elsje G. Otten, Diego Manni, Robin Antrobus, Brian A. Morgan, Thomas von Zglinicki, Diana Jurk, Andrei Seluanov, Vera Gorbunova, Terje Johansen, Jo~ao F. Passos, and Viktor I. Korolchuk. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. 1918 G. HEWITT ET AL. proposed to suppress proteasomal degradation.11 We and positive DDF compared to an ad libitum (AL) feeding regi- others previously demonstrated that this crosstalk can, at men (Fig. 1E–H and Fig. S1I,J).13 Together these observations least in part, be mediated by a prototypical autophagic sub- suggest that SQSTM1 is dynamically recruited to DDF and strate and receptor protein, SQSTM1. SQSTM1 contains a may play a role in DNA repair. Furthermore, clearance of ubiquitin-associated (UBA) domain which recognizes sub- nuclear SQSTM1 foci following DR correlates with the reduc- strates targeted for degradation via both autophagy and pro- tion of DDF suggesting a role for SQSTM1 in mediating the teasomal pathways.12 We have also recently demonstrated effect of autophagy on DNA repair. that SQSTM1 rapidly shuttles between
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