Chemo-/radioresistance of malignant tumors hampers cancer control and increases patient mortality. Efficient repair of damaged DNA is critical for the maintenance of genomic integrity and fidelity of genetic information. In reverse, increased DNA repair capability in cancer cells contributes to chemo-/radioresistance of malignant tumors. DNA double-strand break (DSB) is the most serious DNA damage and is also the principal molecular basis of radiotherapy. Upon DNA damage, the Ku80 is recruited and forms a critical DNA-PK complex at the DSB sites with Ku70 and the catalytic subunit (DNA-PKcs) to initiate DNA repair. How DNA-PK is assembled and activated is not fully understood. Based on the identification of radiation-reduced Ku80 K568 crotonylation through quantitative global lysine crotonylome analysis, we reveal that Ku80 K568 is crotonylated by p300-CBP-associated factor (PCAF). Upon DNA damage, the K568cr is decrotonylated by HDAC8 (Histone deacetylase 8). Decrotonylation of K568cr empties this site for the subsequent SUMOylation of Ku80 by CBX4. The conversion of Ku80 from K568 crotonylation to SUMOylation facilitates the assembly of DNA-PK complex and autophosphorylation of DNA-PKcs S2056, consequently activating the DSB repair. Moreover, mutation disrupting the post-translational modification (PTM) of Ku80 K568 site sensitizes cancer cells to radiotherapy in tumor-bearing nude mice models. This study elucidates the conversion model between two different forms of PTMs in the regulation of DNA-PK complex assembly and DSB repair, highlighting this model’s potential in controlling chemo-/radioresistance of malignant tumors, as well as expands the atlas of therapeutic targets.

DNA methylation is a common endogenous chemical modification in eukaryotic DNA, primarily involving the covalent attachment of a methyl group to the fifth carbon of cytosine residues, leading to the formation of 5-methylcytosine (5mC). This epigenetic modification plays a crucial role in gene expression regulation and genomic stability maintenance in eukaryotic systems. Ionizing radiation (IR) has been shown to induce changes in global DNA methylation patterns, which exhibit significant temporal stability. This stability makes DNA methylation profiles promising candidates for radiation-specific biomarkers. This review systematically examines the impact of IR on genome-wide DNA methylation landscapes and evaluates their potential as molecular indicators of radiation exposure. Advancing the knowledge of radiation-induced epigenetic modifications in radiobiology contributes to a deeper understanding of IR-driven epigenetic reprogramming and facilitates the development of novel molecular tools for the early detection and quantitative risk assessment of radiation exposure.

The present study is aimed at investigating the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) and providing a new perspective in arteriovenous shunt-induced pulmonary arterial hypertension (PAH). PAH was established by an arteriovenous shunt placement performed in rats. Adenovirus(Ad)-CTRP9 and Ad-green fluorescent protein viral particles were injected into the rats through the tail vein. Following 12 weeks, the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured and morphological analysis was conducted to confirm the establishment of the PAH model. The systemic elevation of CTRP9 maintained pulmonary vascular homeostasis and protected the rats from dysfunctional and abnormal remodeling. CTRP9 attenuated the pulmonary vascular remodeling in the shunt group by decreasing the mPAP and RVSP, which was associated with suppressed inflammation, apoptosis, and extracellular matrix injury. In addition, CTRP9 dramatically increased the phosphorylation of AKT and p38-MAPK in the lung tissues of shunt-operated animals. These findings suggest a previously unrecognized effect of CTRP9 in pulmonary vascular homeostasis during PAH pathogenesis.

The purpose of this study was to investigate the influence of C1QL1 on atherosclerosis as well as the transcriptomic alteration of the aorta. While complement C1ql-like 1 (C1QL1) is one of the C1q/tumor-necrosis-factor-related protein (CTRP) family members, also known as CTRP14, and is synthesized and secreted mainly by the brain and adipose tissues, the functional properties of the C1QL1/CTRP14 protein outside the brain and adipocytes remain, however, unknown. In this regard, apolipoprotein E (ApoE) knockout (KO) mice were fed a Western diet and injected with adenovirus (Ad) green fluorescent protein or Ad-C1QL1 through the tail vein for 12 weeks. In contrast with the control cohort, the area of atherosclerotic plaque in ApoE KO mice overexpressing C1QL1 showed no significant difference, and the RNA sequence revealed that there were only 111 differentially expressed genes (DEGs) enriched in 26 signaling pathways of the mRNA profile in the aortic atherosclerosis lesions. This analysis also revealed the expression of several genes related to metabolism, organismal system, and human diseases such as type II diabetes, which are not associated with the formation of atherosclerosis in the aorta. These findings illustrate that C1QL1 is largely dispensable for atherosclerosis formation in ApoE-deficient mice and does not improve atherosclerotic plaque formation in the aorta.

TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast cancer remains unclear. In the current paper, we observed that triple-negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates the proliferation, migration, and invasion of TNBC cells. Our study first obtained RNA-seq data to explore the cellular functions mediated by TAB182 at the genome level in TNBC cells. A transcriptome analysis and in vitro experiments enabled us to identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to olaparib or cisplatin, which can be rescued by silencing GLI2, a gene downstream of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a potential negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting that TAB182 may be a tumor suppressor gene and is associated with increased therapeutic benefits for TNBC patients.