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.

DNA Damage Response and Autophagy: A Meaningful Partnership

“…Therefore, nuclear p62 that accrues from defective autophagy compromises DNA damage repair and genomic integrity. In line with these findings, nuclear levels and co-localization of p62 with DNA damage foci have been reported to increase with aging, underscoring the potential contribution of this pathway to aging and age-related diseases (Hewitt et al, 2016). …”

“…Indeed, there is now significant evidence to suggest that autophagy is required for the function of ‘error-proof’ HR and NER (Liu et al, 2015; Park et al, 2015; Hewitt et al, 2016; Qiang et al, 2016; Wang et al, 2016). Conversely, autophagy-deficient cells rely mostly on the error-prone NHEJ repair process, which may explain the genomic instability observed in experimental mouse models with defective autophagy (Karantza-Wadsworth et al, 2007; Mathew et al, 2007b) and the observation that in human breast, ovarian and prostate cancers, beclin-1 is monoallelically deleted (Aita et al, 1999).…”

“…RAD51 is also regulated by SQSTM1/p62 through filamin A which physiologically responds to DNA damage by recruiting RAD51 to DSBs. Autophagy impairment increases the interaction of p62 with filamin A, causing proteasomal degradation of both filamin A and RAD51 (Hewitt et al, 2016). Therefore, nuclear p62 that accrues from defective autophagy compromises DNA damage repair and genomic integrity.…”

Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

“…Autophagy can clear nuclear remnants positive for γH2AX that arise upon severe cell cycle disturbance [54]. Furthermore, autophagy directs the nucleotide excision repair complex to sites of UV induced DNA damage [55], a process involving p62 [56] thus, disturbed repair or clearance of damaged DNA may contribute to the increase in actual DNA damage we observed.…”

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

“…To clarify if autophagy-associated proteins [14] are detectable in these nuclear inclusions we looked for the presence of the proteins p62/sequestosome1, ubiquitin, LC3B, cathepsin B and cathepsin D by immunohistochemistry. Notably, p62 is also involved in several biological processes [15,16] including NFκB activity, cell proliferation [17,18], apoptosis [19], Keap1-Nrf2 system [20], DNA repair [21,22] and is associated with several cancer types [23][24][25][26][27][28][29][30][31]. In this study we investigated the occurrence of nuclear inclusions in hepatocytes of patients with HCC, characterised the inclusions by means of electron microscopy and immunohistochemistry, and explored if these inclusions have any impact on patient survival.…”