title: SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair.
abstract: SQSTM1/p62 (sequestosome 1) selectively targets polyubiquitinated proteins for degradation via macroautophagy and the proteasome. Additionally, SQSTM1 shuttles between the cytoplasmic and nuclear compartments, although its role in the nucleus is relatively unknown. Here, we report that SQSTM1 dynamically associates with DNA damage foci (DDF) and regulates DNA repair. Upon induction of DNA damage SQSTM1 interacts with FLNA (filamin A), which has previously been shown to recruit DNA repair protein RAD51 (RAD51 recombinase) to double-strand breaks and facilitate homologous recombination (HR). SQSTM1 promotes proteasomal degradation of FLNA and RAD51 within the nucleus, resulting in reduced levels of nuclear RAD51 and slower DNA repair. SQSTM1 regulates the ratio between HR and nonhomologous end joining (NHEJ) by promoting the latter at the expense of the former. This 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.
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Hewitt
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Carroll
authors.affiliation: c Department of Biology , University of Rochester , Rochester , NY USA.
authors.forename: Rezazadeh
authors.initials: R
authors.lastname: Sarallah
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Clara
authors.initials: C
authors.lastname: Correia-Melo
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Mikołaj
authors.initials: M
authors.lastname: Ogrodnik
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Glyn
authors.initials: G
authors.lastname: Nelson
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Elsje G
authors.initials: EG
authors.lastname: Otten
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Manni
authors.affiliation: b Cambridge Institute for Medical Research , Cambridge University , Cambridge , UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Morgan
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Jurk
authors.affiliation: c Department of Biology , University of Rochester , Rochester , NY USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
authors.affiliation: c Department of Biology , University of Rochester , Rochester , NY USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: d Molecular Cancer Research Group , Department of Medical Biology , University of Tromsø - The Arctic University of Norway , Tromsø , Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: João F
authors.initials: JF
authors.lastname: Passos
authors.affiliation: a Institute for Cell and Molecular Biosciences , Newcastle University , Newcastle upon Tyne , UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
mesh_terms: D000818:Animals; D001343:Autophagy; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D064448:Filamins; D007700:Kinetics; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis; D051135:Rad51 Recombinase / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D064448:Filamins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D051135:Rad51 Recombinase; D046988:Proteasome Endopeptidase Complex
keywords: DNA damage; SQSTM1; aging; autophagy; homologous recombination; nonhomologous end joining