SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair

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.

SQSTM1/p62（sequestosome 1）可选择性靶向多泛素化蛋白，通过巨自噬与蛋白酶体通路介导其降解。此外，SQSTM1可在细胞质与细胞核区室之间穿梭，但其在细胞核中的功能尚不清楚。本研究发现，SQSTM1可与DNA损伤灶（DNA damage foci, DDF）动态结合，并调控DNA修复过程。在DNA损伤诱导后，SQSTM1会与FLNA（filamin A，细丝蛋白A）结合；此前已有研究表明，FLNA可将DNA修复蛋白RAD51（RAD51重组酶）招募至双链断裂位点，并促进同源重组（homologous recombination, HR）。SQSTM1可促进细胞核内FLNA与RAD51的蛋白酶体降解，进而导致细胞核内RAD51水平降低，DNA修复速率减慢。SQSTM1通过优先促进非同源末端连接（nonhomologous end joining, NHEJ）、抑制同源重组，来调控HR与NHEJ之间的比例。这种依赖于SQSTM1的机制介导了巨自噬对DNA修复的调控作用。此外，SQSTM1的核定位及其与DNA损伤灶的结合能力会随衰老进程增强，而延长寿命的膳食限制可阻断这一过程；这表明本研究揭示的机制失衡，可能会促进衰老及年龄相关疾病的发生。