SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair.
SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair.
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DOI：
10.1080/15548627.2016.1210368
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发表时间：
2016-10-02
期刊：
影响因子：
13.3
通讯作者：
Korolchuk VI
中科院分区：
文献类型：
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作者：
Hewitt G;Carroll B;Sarallah R;Correia-Melo C;Ogrodnik M;Nelson G;Otten EG;Manni D;Antrobus R;Morgan BA;von Zglinicki T;Jurk D;Seluanov A;Gorbunova V;Johansen T;Passos JF;Korolchuk VI
SQSTM1/p62(隔离体1)通过宏自噬和蛋白酶体选择性地靶向多泛素化蛋白进行降解。此外，SQSTM1穿梭于细胞质和细胞核之间，尽管它在细胞核中的作用相对未知。在这里，我们报道了SQSTM1动态地与DNA损伤焦点(DDF)结合并调节DNA修复。在诱导DNA损伤时，SQSTM1与FLNA(细丝蛋白A)相互作用，先前已被证明招募DNA修复蛋白RAD51(RAD51重组酶)进行双链断裂并促进同源重组(HR)。SQSTM1促进细胞核内Flna和RAD51的蛋白酶体降解，导致核RAD51水平降低和DNA修复速度减慢。SQSTM1通过促进非同源末端连接(NHEJ)而调节HR和NHEJ之间的比例，而不是前者。这种依赖于SQSTM1的机制介导了宏自噬对DNA修复的影响。此外，SQSTM1的核定位及其与DDF的关联随着年龄的增加而增加，并通过延长寿命的饮食限制来防止，这表明这里发现的机制的不平衡可能导致衰老和与年龄相关的疾病。
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.