MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase)

Two patients carried mutations in MBD4, suggesting it may contribute to early-onset disease. The high frequency of rare variants in high- or intermediate-risk genes highlights the importance of including such genes in genetic tests, as they may have implications for future risk in the adolescent patients and their at-risk relatives.

Pathway enrichment revealed associations with cell cycle regulation (E2F3, MKI67), DNA repair (BRCA2), and transcriptional control (MED1), with six priority genes (MED1, BRCA2, E2F3, PITPNB, H1-1, and FARP2) showing established breast cancer relevance. This externally validated 17-gene signature provides a biologically grounded tool for NAC response prediction in precision oncology.

MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.

This important function has resulted in MBD4 being implicated in various human health disorders including MBD4-associated neoplasia syndrome and cancer resistance to 5-fluorouracil treatment...This proposal is fully consistent with experimental crystallographic, mutagenic, stereoscopic, and kinetic data, and aligns the MBD4 catalytic pathway with that characterized for several other monofunctional DNA glycosylases. By furthering our knowledge of MBD4 catalysis, this work will aid in the future development of treatments for MBD4-related genetic disorders and the rational design of transition state mimic inhibitors to enhance existing cancer therapies.

The observed effect was ESR1-dependent and effectively blocked by tamoxifen, revealing a ligand-independent activation mechanism...The presence of PSNPs also mitigated AgNPs-induced reduction of BRCA1 expression. This study highlights how nanomaterial-induced ESR1 activation can lead to enhanced epithelial-mesenchymal transition and cell cycle progression, suggesting potential adverse effects of nanomaterials in ER+ cancer proliferation via protein kinase-mediated ESR1 modulation.

In this issue of Cancer Cell, Wei et al. uncover MED1-driven ecDNA super-enhancers as regulatory hubs and show that disrupting ecDNA-containing condensates selectively impairs transcription and induces apoptosis in a cancer-type-specific manner.

A second strong predisposition to CRC is MAP, characterized by biallelic pathogenic variants in the MUTYH gene, with a phenotype similar to FAP. This mini review focuses on potential approaches to improve the diagnosis of patients in whom pathogenic variants in the APC and MUTYH genes are not detected by routine testing.

The performance interaction and visualization of SEA version 4.0 enable genomic and cross-species comparisons, revealing complex genomic interactions and becoming an indispensable resource for decoding the mechanisms of SE in development and disease. Access freely at http://sea4.edbc.org.

Functionally, ER+ BC cells with deacetylated MED1 exhibit faster growth and enhanced stress resistance in culture and in an orthotopic mouse model. These findings advance our understanding of Pol II regulation under cellular stress and potentially suggest therapeutic strategies targeting oncogenic transcription driven by MED1 and Mediator.

This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.