MRE11A (MRE11 homolog, double strand break repair nuclease)

The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP...The only SNP reaching genome-wide significance (p < 5 × 10-8) was in BNC2. The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets.

but direct functional impact on gene expression was not observed in this study. The observed promoter methylation and gene expression alterations provide preliminary evidence of epigenetic modifications in response to chronic LDIR.

Knocking out Ptbp2 in CML cell lines and patient samples decreased Polk levels; when treated with hydroxyurea, these samples exhibited increased DNA damage, evidenced by long comet tails and elevated γH2AX foci, a DNA damage marker; however, re-expressing Polk in Ptbp2-KO cells restored the phenotype...Cells with high levels of Ptbp2 and Polk showed increased sister chromatid exchanges and BrdU incorporation in ex vivo tests, while multinucleated cells with multipolar spindles appeared in in vivo tests. Our results confirm the key role of the Ptbp2-Polk-MRE11 axis in promoting genomic instability and supporting the survival of cells with higher malignancy.

Combined inactivation of ATR and Polθ synergistically kills cancer cells under high replication stress with minimal toxicity to normal cells. Together, our study provides fundamental insights into the MMEJ mechanism and offers new strategies for cancer treatment.

Together, we propose that CTCF and cohesin co-binding can impede replication fork progression, leading to DNA damage and DDR activation. However, in cells with defective DDR, these lesions may promote genomic instability at CBSs.

In contrast to typical results obtained through photon irradiation, where γH2AX and H3K9me3 markers were well separated, the results obtained here also showed a close spatial proximity ("co-localization") in many cases (minimum distance of markers = marker size), even with the strictest co-localization distance threshold (20 nm) for γH2AX and H3K9me3. The data support the results from the literature where only one DSB induced by low-dose low LET irradiation (<100 mGy) can remain without heterochromatin relaxation for subsequent repair.

From this dataset, we validated both positive and negative interactions under basal and irradiated conditions, including a synthetic lethal relationship between MRE11A and the E3 ligase UBR5, a role for Ku70/80 in preventing unscheduled nuclease activity at telomeres, an IR-specific vulnerability upon co-disruption of CYREN and PARG, and a link between CYREN-mediated radioresistance and innate immunity. This resource enables mechanistic insight and reveals therapeutic vulnerabilities in DNA-repair-deficient cancers.

IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.

Moreover, MRE11 K393 deacetylation by SIRT2 promoted ATM-dependent signaling. Our findings define a mechanism regulating MRE11 binding to DNA through SIRT2 deacetylation, elucidating a critical upstream signaling event directing MRE11 function in the DDR and providing insight into how SIRT2 dysregulation leads to genomic instability and tumorigenesis.

Abasic sites, especially from methyl-cytosine metabolism, put replication forks at risk of breaking, amplifying the need for RAD51-mediated defense. Such redefinition of homologous recombination protein function as part of an anticipatory surveillance and protective system, rather than a repair-only module, bears important implications for understanding tumorigenesis, therapy resistance, and aging.

Notably, CHAMP1 deficiency induces synthetic lethality with FANCM inhibition in ALT-positive tumor cells, and the CHAMP1 complex is essential for the survival of CCNE1-amplified ovarian cancers. These findings uncover a heterochromatin-based mechanism of replication fork stabilization and suggest that CHAMP1 may represent a candidate therapeutic vulnerability in cancers with elevated RS.

Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC.