Genomics, Proteomics & Bioinformatics•2024•DOI: 10.1093/gpbjnl/qzae016
Ribonuclease P (RNase P) was first described in the 1970’s as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025063
Homologous recombination (HR) is crucial for the high-fidelity repair of DNA double-strand breaks (DSBs), ensuring the maintenance of genome stability. In this study, we show that FOXD3 interacts with poly (ADP-ribose) polymerase 1 (PARP1) and is recruited to DSBs in a PARP1-dependent manner. FOXD3 directly binds to the DSB repair protein MRE11 and promotes its recruitment to DSB sites, ensuring proper end resection. Inhibition of FOXD3 expression compromises HR-mediated DSB repair and chromosome stability and sensitizes cancer cells to ionizing radiation. Collectively, our findings demonstrate that FOXD3 promotes HR-mediated DSB repair and genome stability.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025063
Homologous recombination (HR) is the high-fidelity pathway for repairing DNA double-strand breaks (DSBs) during S/G2 phases, and its dysfunction drives genomic instability and cancer progression. The MRN complex (MRE11/RAD50/NBS1) initiates DNA end resection, a critical step for HR, but how MRE11 recruitment and activity are regulated remains incompletely defined. Here we identify FOXD3 as a novel HR factor that interacts with PARP1 and is recruited to DSB sites in a PARP1-dependent manner. FOXD3 directly binds MRE11 and promotes its recruitment to DSBs, ensuring proper end resection. Depletion of FOXD3 impairs HR-mediated DSB repair, reduces chromosome stability, and sensitizes cancer cells to ionizing radiation. These findings establish FOXD3 as a key regulator of MRE11-mediated end resection and suggest that FOXD3 expression levels could serve as a biomarker for HR proficiency and as a therapeutic target to induce synthetic lethality with PARP inhibitors or radiotherapy. The study provides mechanistic insight into the early steps of HR and highlights the clinical potential of targeting FOXD3 in cancers with HR defects.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025028
ISGylation is the post-translational modification of protein substrates covalently conjugated with the ubiquitin-like protein interferon-stimulated gene 15 (ISG15). Initially linked to antiviral immunity, recent evidence highlights important roles for ISGylation in various biological processes, such as maintaining genomic stability, promoting tumourigenesis, and being involved in other pathological conditions. In this review, we examine the molecular mechanisms underlying ISGylation, its interplay with other post-translational modifications, and its involvement in diverse biological and pathological processes. We propose future research directions to advance the field and discuss how ISGylation might be harnessed to ensure human health, particularly genome instability-associated diseases. The modification is catalyzed by an enzymatic cascade analogous to ubiquitination, involving the E1-activating enzyme UBA7 (Ube1L), E2-conjugating enzyme UbcH8, and E3 ligases such as HERC5, TRIM25, and RNF213. ISG15 is a 15 kDa protein comprising two tandem ubiquitin-like domains, initially synthesized as a 165-amino-acid precursor that undergoes processing by a human ortholog of yeast ubiquitin-specific protease Ubp1 to yield a mature 156-amino-acid protein. A conserved C-terminal motif (151-LRLRGG-156) is essential for target protein conjugation. ISGylation is reversed by the protease USP18 (UBP43). The modification is induced by type I interferons, lipopolysaccharide, DNA damage, and viral or bacterial infections. Beyond antiviral defense, ISGylation regulates DNA damage response, cell cycle progression, and immune signaling. Dysregulated ISGylation is implicated in cancer, inflammatory diseases, and viral pathogenesis. The review synthesizes current knowledge and outlines therapeutic opportunities targeting ISGylation for genome instability-associated diseases.