RIF1 (Replication Timing Regulatory Factor 1)

A genetic diagnostic model constructed based on ten genes (RIF1, GDPD5, DBNDD1, RCCD1, CLDN5, ASCL2, IFITM3, IFITM1, SMPDL3A, and SUCLG2) demonstrates strong predictive performance. This model holds significant potential for the early diagnosis and intervention of colorectal cancer, contributing to the implementation of third-tier prevention strategies.

We further show that the Ser/Lys-rich cassette stabilized a novel phase separation activity of the RIF1 CTD and enhanced RIF1-L chromatin retention, which was reversed by cyclin-dependent kinase 1-dependent phosphorylation of the RIF1 CTD in response to G2 DNA damage checkpoint inhibition. These combined findings suggest DNA damage-dependent RIF1 alternative splicing contributes to RIF1 functional diversification in genome protection.

We posit that SCAI/REV3 may be required to replicate through and rescue stalled replication forks at fragile genomic regions. Failure to do so leads to increased DNA breakage and genomic instability.

By linking germline variants to more biologically relevant gene targets and somatic processes, our results align more closely with established epidemiological and environmental risk factors for lung cancer, including a potential genetic explanation for the environmental interaction of caffeine and smoking in LC risk. This highlights the value of integrating 3D genome architecture and tissue-specific expression to refine our understanding of cancer susceptibility.

These surprising results suggest that GSK3β may select between NHEJ and HR DNA repair pathways. Additionally, these data support targeting the GSK3β/53BP1 axis to enhance PARP inhibitor efficacy in solid tumors, regardless of BRCA1 status.

Importantly, both genetic and pharmacologic disruption of the GSK3B-53BP1 axis sensitizes tumors to PARP inhibitors (PARPi) independently of BRCA1 status. Together, these findings reveal a GSK3B-dependent mechanism that regulates DSB repair pathway choice and provide a rationale for targeting this axis to enhance PARPi efficacy in solid tumors regardless of BRCA1 status.

This study identified 13 new susceptibility genes significantly associated with PCa risk and provided new insights into the genetic basis of PCa, contributing to a more comprehensive understanding of its complex genetic structure.

We demonstrate quantitative changes in size, relative abundance and spatial arrangement of nanoscale DNA synthesis events upon chemotherapeutic treatment, CDC6 oncogene expression and loss of chromatin organiser RIF1. The flexibility, precision and modular design of 3D-SPARK helps bridging the gap between spatial cell biology, genomics, and 2D fibre-based replication studies in health and disease.

Basal breast cancer also shows exon exclusion, but unlike other subtypes, it shows no short-exon bias. Surprisingly, however, in basal breast cancer, RIF1 Exon 31 is not consistently excluded, which may impact prognosis since RIF1-Long protects against replication stress.

Analysis of p53 missense mutations (R248W, R273C, G245S) revealed mutation-specific effects on 53BP1 and RIF1 recruitment, with G245S retaining wild-type-like 53BP1 recruitment but still exhibiting enhanced BRCA1 foci formation. Given the widespread activation of NHEJ throughout the cell cycle, especially in response to radiotherapy and chemotherapy, gaining insight into how p53 mutations affect this response is vital for developing future therapeutic strategies.

Finally, DNA-PKcs kinase inhibition causes marked radiosensitivity, which is not additive with loss of 53BP1 and RIF1. Altogether, 53BP1/RIF1 and DNA-PKcs show distinct genetic interactions with diverse DSB repair outcomes.

It is hypothesized that Tubercidin induces NSs condensation, affecting alternative splicing of cell death genes, potentially worsening ischemic cardiomyocytes' damage. Therefore, a cautious clinical use of Tubercidin for ischemic cardiomyopathy patients is advised to reduce cardiotoxicity risks.