Wei-Guo Zhu

DNA double strand breaks (DSBs) are repaired through distinct pathways, with homologous recombination (HR) favored when DNA ends undergo extensive resection. Although cytoplasmic N7-methylguanosine (m7G)-modified RNA increases after UV-induced single-strand breaks, its role in DSB repair (including HR) remains unclear. Here, we show that m7G-modified RNA accumulates at DSB sites, where it recruits the m7G reader protein Quaking (QKI)5, to selectively promote HR. Mechanistically, QKI5 directly interacts with MRE11 and enhances its DNA binding affinity, thereby facilitating DNA end resection. Depletion of QKI5 impairs recruitment of the MRE11–RAD50–NBS1 complex to DSBs and reduces HR repair efficiency. Moreover, elevated QKI5 expression is associated with resistance to radiotherapy in both mouse models and clinical cohorts. Together, these findings identify the m7G RNA–QKI5–MRE11 axis as a regulator of HR pathway choice and suggest QKI5 as a promising therapeutic target in cancer treatment.

The Ku heterodimer, composed of Ku70 and Ku80 subunits, is essential for non-homologous end joining (NHEJ). However, the precise mechanisms underlying its assembly and activation remain unclear. Here, we uncovered a novel mechanism for the formation of Ku heterodimer by Ku70 deacetylation. Mechanistically, TIMELESS, as a scaffold protein, bridges SIRT1 and Ku70 to assemble the TIMELESS-SIRT1-Ku70 (TSK) complex. In the presence of TIMELESS, the interaction between SIRT1 and Ku70 was remarkably increased following ionizing radiation (IR), thereby enabling SIRT1-mediated deacetylation of Ku70 at K265 and K331 and promoting the Ku heterodimer formation. The assembly of Ku heterodimer is a prerequisite for initiating and enhancing NHEJ repair efficiency. Therefore, depletion of TIMELESS markedly reduced the Ku heterodimer assembly and impaired NHEJ efficiency. Importantly, targeting TIMELESS sensitizes cancer cells and xenograft mouse models to radiation, highlighting its potential as a therapeutic target for improving radiotherapy outcomes.

The core transcriptional regulatory program governed by a small set of master transcription factors is pivotal for establishing context-specific cellular features. Here, we report the roles of master factor MYC in actively regulating cancer-type specific super-enhancer activity and orchestrating a super-enhancer-dependent core transcriptional regulatory circuitry consisting of MYC, ETS2, and FOXP1 in colorectal cancer. The core regulatory module selectively promotes the transcription of super-enhancer-controlled genes in cooperation with co-activator BRD4, and perturbing the core circuitry factors sensitizes colon cancer cells to BET inhibition. LGR5, a key stemness gene, is activated in colorectal cancer at least in part by a circuitry-controlled distal super-enhancer, which is a frequently gained super-enhancer in colorectal cancer and required for metastasis propagation. These findings reveal a hierarchical transcription regulatory network in colorectal cancer, pinpoint distal enhancer as an important fuel for LGR5 overexpression in cancer, and provide insights for precisely targeting detrimental transcription events in therapy.

Chronic inflammation is a fundamental driver of cancer development, linking persistent immune activation to genomic instability, microenvironmental remodeling, and malignant transformation. In inflammation‐associated malignancies such as colitis‐associated cancer (CAC) and metabolic dysfunction–associated fatty liver disease–related hepatocellular carcinoma (MAFLD‐HCC), sustained inflammatory signaling integrates tissue injury with oncogenic pathways to promote tumor initiation and progression. Importantly, these cancers arise through prolonged preneoplastic stages, during which dysregulated immune and inflammatory responses not only drive malignant transformation but also create opportunities for cancer prevention and early disease interception. CAC and MAFLD‐HCC share convergent mechanisms, including IL‐6/STAT3 and NF‐κB activation, cytokine‐driven survival signaling, and cooperation with genetic alterations in APC, KRAS, and TP53. A critical but often underappreciated dimension of this process is the failure of endogenous immunoregulatory systems that normally restrain excessive inflammation. Among these, the negative regulator of immune cells TIPE2 plays an important role in limiting inflammatory signaling, and its reduced activity contributes to the persistence of a tumor‐promoting inflammatory microenvironment that supports both disease initiation and progression. This review synthesizes the shared inflammatory, immunologic, and microenvironmental mechanisms underpinning CAC and MAFLD‐HCC, with a particular emphasis on how impaired immune regulation drives the transition from chronic inflammation to cancer. We further highlight therapeutic and preventive strategies targeting inflammation‐driven pathways, underscoring the dual relevance of immune modulation for cancer prevention in chronic inflammatory disease and for the treatment of established malignancy.

Suppressors of variegation 3-9 homolog 1 (SUV39H1), the enzyme responsible for establishing histone H3 lysine 9 trimethylation (H3K9me3) marks in heterochromatin, is frequently dysregulated in cancers. However, the mechanisms underlying SUV39H1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 1 (PRMT1) directly interacts with SUV39H1 and dimethylates it at arginine 378 (R378). PKC signaling-mediated phosphorylation of SUV39H1 at S391 enhances this interaction, thereby promoting its methylation. Notably, PRMT1 binds to SUV39H1 with higher affinity and binding free energy than MDM2, causing a structural clash that blocks MDM2-mediated ubiquitination of SUV39H1. Moreover, methylated SUV39H1 exhibits enhanced H3K9me3 methyltransferase activity and promotes tumor cell growth. A SUV39H1-derived peptide (TAT-SUV-peptide) disrupts the interaction between PRMT1 and SUV39H1, thereby reducing SUV39H1 methylation. Administration of TAT-SUV-peptide remarkably suppresses mammary tumor growth. Taken together, our findings reveal a critical phosphorylation–methylation–ubiquitination axis in controlling SUV39H1 stability and highlight its therapeutic potential through targeting SUV39H1 methylation.

Recombination Activation Protein 51 (RAD51) is the key recombinase in the homologous recombination (HR) repair pathway. Given its high expression in many cancers and its association with poor prognosis, RAD51 represents a compelling therapeutic target for cancer treatment. Here, we report the development of first-in-class proteolysis-targeting chimeras (PROTACs) directed to RAD51, based on the RAD51-targeting small-molecule inhibitors RI-1 and RI-2. Among them, SZU305 (15b) showed potent and selective RAD51 degradation and antiproliferative effects in multiple liver cancer cell lines, inducing near-complete RAD51 depletion in both SK-HEP-1 and Huh-7 cancer cells. Mechanistically, 15b reduces HR efficiency and impairs DNA damage repair, thereby enhancing chemoradiation sensitivity. In vivo, SZU305 showed strong antitumor activity without apparent toxicity, particularly when combined with sorafenib or irradiation in a Huh-7 xenograft model. These findings highlight the therapeutic potential of RAD51 degradation as a novel strategy to overcome drug resistance in liver cancer.