Ying Jiang

Cellular senescence, a state of permanent cell cycle arrest, contributes to tissue dysfunction and aging through the accumulation of apoptosis-resistant senescent cells. Although the transcription factor FOXO4 is known to enhance senescent cell survival, the mechanisms regulating its stability have remained unclear. Here, we identify a DNA damage response (DDR)-driven CHK2-USP37-FOXO4 axis essential for maintaining the apoptotic resistance of senescent cells. We demonstrate that FOXO4 protein stability is elevated in stress-induced senescent cells, resulting from reduced ubiquitin-proteasomal degradation. A deubiquitinase screen identified USP37 as the key enzyme stabilizing FOXO4 through direct interaction and removal of K48-linked polyubiquitin chains. Depletion of USP37 destabilizes FOXO4 and sensitizes senescent cells to apoptosis. Mechanistically, persistent DDR signaling during senescence activates CHK2, which phosphorylates USP37 at Thr589, thereby enhancing its binding to FOXO4. Importantly, ablation of USP37 in senescent cells increases the rate of apoptosis, a phenotype that is rescued by FOXO4 reexpression. Together, our work unveils USP37 as a CHK2-regulated stabilizer of FOXO4 that maintains the apoptotic resistance of senescent cells, suggesting the CHK2-USP37-FOXO4 axis as a therapeutic target for age-related pathologies.

Impairments in DNA repair mechanisms undermine genomic integrity, accelerating the aging process and elevating the risk of age-related diseases in both murine models and humans. Despite the recognized link between DNA repair and aging, empirical evidence supporting the lifespan and healthspan extension through enhanced DNA repair is lacking. This knowledge gap is attributed to the complex interplay of numerous DNA repair genes involved in maintaining genomic stability, making it challenging to pinpoint specific pathways and factors that could be targeted for lifespan and healthspan improvements. In this study, we generated a knock-in mouse model overexpressing XRCC4 and DNA LIG4, key components of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks. Our findings reveal that augmenting NHEJ is a viable anti-aging strategy in mammals, as evidenced by extended lifespan and improved healthspan in both wild type mice and LmnaG609G/+ progeroid mice. Additionally, enhanced NHEJ activity improves cardiac, motor, and cognitive functions, as well as bone quality in aged mice. Transcriptomic and epigenetic analysis across different organs indicates significant downregulation in inflammatory responses and upregulation of pathways associated with maintaining organ homeostasis and function, further supporting the role of DNA repair in modulating aging and age-related diseases. Our data underscore the potential of targeting DNA repair pathways as a strategy to counteract aging and its associated health decline.

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and limited therapeutic options. DNA damage-based radiotherapy plays a significant role in the treatment of TNBC. However, radioresistance continues to pose a significant challenge, often resulting in the unsuccessful outcome of radiation therapy for patients with TNBC. Type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), a key enzyme in phosphoinositide metabolism, is associated with poor prognostic outcomes in TNBC. Here, we discovered that PIPKIγ overexpression significantly boosts nonhomologous end joining (NHEJ), a principal mechanism for repairing DNA double-strand breaks (DSBs). This enhancement of NHEJ confers increased radioresistance in TNBC. At the molecular level, PIPKIγ directly interacts with LIG4, a crucial NHEJ component, and strengthens its interaction with XRCC4, a key regulator of LIG4 nuclear translocation. This facilitates LIG4’s nuclear translocation, improving DNA repair efficiency and genomic stability in TNBC cells. Furthermore, elevated PIPKIγ levels enhance radioresistance in TNBC cells and tumors in xenograft models, whereas depleting PIPKIγ has the opposite effects. These insights reveal a new mechanism by which PIPKIγ promotes radioresistance through the facilitation of DSBs repair in TNBC. Collectively, our findings suggest that the PIPKIγ-LIG4 interaction represents a potential therapeutic target for improving radiotherapy efficacy in TNBC patients.

As the major DNA sensor that activates the STING-TBK1 signaling cascade, cGAS is mainly present in the cytosol. A number of recent reports have indicated that cGAS also plays critical roles in the nucleus. Our previous work demonstrated for the first time that cGAS is translocated to the nucleus upon the occurrence of DNA damage and inhibits homologous recombination (HR), one of the two major pathways of DNA double strand break (DSB) repair. However, whether nuclear cGAS regulates the other DSB repair pathway, nonhomologous end joining (NHEJ), which can be further divided into the less error-prone canonical NHEJ (c-NHEJ) and more mutagenic alternative NHEJ (alt-NHEJ) subpathways, has not been characterized. Here, we demonstrated that cGAS tipped the balance of the two NHEJ subpathways toward c-NHEJ. Mechanistically, the cGAS-Ku80 complex enhanced the interaction between DNA-PKcs and the deubiquitinase USP7 to improve DNA-PKcs protein stability, thereby promoting c-NHEJ. In contrast, the cGAS-Ku80 complex suppressed alt-NHEJ by directly binding to the promoter of Polθ to suppress its transcription. Together, these findings reveal a novel function of nuclear cGAS in regulating DSB repair, suggesting that the presence of cGAS in the nucleus is also important in the maintenance of genome integrity.

Yu Chen, Xiaoyu Xu, Zhixi Chen, Lingjiang Chen, Ying Jiang, Zhiyong Mao; Circadian factors CLOCK and BMAL1 promote nonhomologous end joining and antagonize cell

Cyclic GMP–AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.

In order to improve the forecasting accuracy of monthly electricity sales and the refined operation management of power users. A management method of power transformer operation system is proposed. Through the establishment and use of the management and control working model of the special transformer, the forecasting accuracy of monthly electricity sales is improved, the early warning of electricity charges is realized to avoid arrears, and abnormal situations such as current loss and voltage loss of the special transformer users can be found and handled in time, thus preventing the loss of electricity and current. Using the mobile Internet and GPS positioning, the staff can query the equipment and geographical information of distribution GIS system in real time while patrolling the distribution circuit. Combined with the regular inspection of special transformer users, a series of measures have been implemented to improve the refined level of power transformer user management and provide better and better power supply services for special transformer users.