TY - JOUR
T1 - SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair
AU - Hewitt, Graeme
AU - Carroll, Bernadette
AU - Sarallah, Rezazadeh
AU - Correia-Melo, Clara
AU - Ogrodnik, Mikołaj
AU - Nelson, Glyn
AU - Otten, Elsje G.
AU - Manni, Diego
AU - Antrobus, Robin
AU - Morgan, Brian A.
AU - von Zglinicki, Thomas
AU - Jurk, Diana
AU - Seluanov, Andrei
AU - Gorbunova, Vera
AU - Johansen, Terje
AU - Passos, João F.
AU - Korolchuk, Viktor I.
PY - 2016/10/2
Y1 - 2016/10/2
N2 - 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.
AB - 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.
KW - aging
KW - autophagy
KW - DNA damage
KW - homologous recombination
KW - nonhomologous end joining
KW - SQSTM1
UR - http://www.scopus.com/inward/record.url?scp=84983354246&partnerID=8YFLogxK
U2 - 10.1080/15548627.2016.1210368
DO - 10.1080/15548627.2016.1210368
M3 - Article (Academic Journal)
C2 - 27391408
AN - SCOPUS:84983354246
SN - 1554-8627
VL - 12
SP - 1917
EP - 1930
JO - Autophagy
JF - Autophagy
IS - 10
ER -