Ask about this productRelated genes to: BTBD12 antibody
- Gene:
- SLX4 NIH gene
- Name:
- SLX4 structure-specific endonuclease subunit
- Previous symbol:
- BTBD12
- Synonyms:
- KIAA1784, KIAA1987, FANCP
- Chromosome:
- 16p13.3
- Locus Type:
- gene with protein product
- Date approved:
- 2003-12-15
- Date modifiied:
- 2019-04-23
Related products to: BTBD12 antibody
Related articles to: BTBD12 antibody
- The synthetic lethal interaction between poly(ADP-ribose) polymerase (PARP) inhibition and homologous recombination (HR)-deficiency, particularly in BRCA1/2-mutant tumors, has emerged as an effective strategy for cancer therapy. GEN1, a structure-selective endonuclease that resolves Holliday junctions (HJs) during HR, represents an attractive antitumor target. However, effective small-molecule GEN1 inhibitors have yet to be reported. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform and identified the natural flavonoid scutellarin (SCU) as a specific inhibitor of human GEN1. SCU selectively inhibited GEN1 endonuclease activity against both 5'-flap and HJ DNA substrates, with no effect on other tested structure-selective endonucleases, such as SLX1-SLX4 and MUS81-EME1. Mechanistic studies showed that SCU does not disrupt GEN1-DNA binding but instead binds to the catalytic center of GEN1, thereby inhibiting its endonuclease activity. In HCT116 cells, SCU acted in synergy with the PARP inhibitor olaparib to markedly impair DNA double-strand break (DSB) repair, increase γH2AX accumulation, induce G2/M cell cycle arrest, and suppress cell migration. Notably, the SCU/olaparib combination produced robust synthetic lethality in both HCT116 and HeLa cells, resulting in substantial inhibition of cell viability and colony formation. Our study identifies SCU as a novel selective GEN1 inhibitor, and suggests a new therapeutic strategy that combines GEN1 inhibitors with PARP inhibitors for cancer treatment. - Source: PubMed
Publication date: 2026/08/18
Zhan BinbinZhong YichenChen XueningDai YijunDu LiyangLin ZhonghuiLi Zuoan - MUS81 is a structure-specific endonuclease that processes DNA intermediates during mitosis and in S-phase following replication stress. It plays a crucial role in cleaving deprotected reversed forks in BRCA2-deficient cells. However, how MUS81 is regulated during replication stress in human cells remains unknown. Our study reveals that CHK2 binds to the MUS8-EME2 complex in S-phase through the FHA domain and positively regulates the formation of DSBs in response to persistent or pathological replication stress. Mechanistically, our cellular and biochemical data identify a dual-site phosphorylation regulatory mechanism involving priming at the CDK2 site S95 followed by CHK2-dependent modification of the activatory site S97. Phosphorylation of MUS81 does not affect recruitment to the stalled forks but is crucial for the replication stress-dependent association with SLX4 in S-phase. At deprotected forks, in BRCA2-depleted cells, the CHK2-MUS81 complex assembles downstream of fork reversal and degradation, and CHK2-dependent phosphorylation is essential for replication fork recovery and viability. Together, our findings elucidate a novel regulatory mechanism of the MUS81 complex in S-phase and reveal a previously unrecognized role of the ATM-CHK2 axis in responding to persistent replication fork arrest or fork deprotection in the absence of BRCA2. - Source: PubMed
Malacaria EvaFiglioli CarolinaPalma AnitaHonda MasayoshiValenzisi PasqualeCasella MarialuisaCamerini SerenaPucci FabioRinalducci SaraSemproni MaurizioSpies MariaFranchitto AnnapaolaPichierri Pietro - Medulloblastoma (MB) with MYC amplification is associated with aggressive clinical behavior and a high risk of metastatic dissemination. Extraneural metastasis (ENM), although rare in the modern treatment era, remains a devastating manifestation linked to poor survival. We report a pediatric case of MB with high-level MYC amplification and NanoString-based molecular subgrouping confirming Group 3 identity in a 9-year-old girl who developed rapidly progressive and widespread ENMs involving the bone marrow, liver, lymph nodes, and peritoneum shortly after craniospinal irradiation. Planned adjuvant chemotherapy could not be initiated because of persistent cytopenias associated with marrow infiltration during disease progression. Targeted next-generation sequencing identified somatic alterations in PTEN, ARID2, and ERCC6, as well as a heterozygous germline SLX4 variant of uncertain clinical significance. While these findings do not establish a causal role in tumor progression, they further illustrate the molecular complexity of high-risk MB. The clinical course observed in this patient is consistent with prior reports linking MYC amplification to aggressive metastatic behavior. This case underscores the challenges of managing molecularly high-risk MB and highlights the importance of comprehensive molecular characterization and timely systemic therapy. - Source: PubMed
Publication date: 2026/07/04
Chen LianLi ShaoqunWang LichaoLi HainanCai LinboLai Mingyao - Inducing the transition of tumor cells into normal hepatocyte-like cells represents a promising therapeutic strategy for hepatocellular carcinoma (HCC). However, safe and effective inducers are currently lacking, and the underlying mechanisms remain poorly understood. This study aimed to investigate whether tumor supernatant (Tsn) under mild hyperthermia conditions could induce the transition of HepG2 cells into normal hepatocyte-like cells and to elucidate the potential mechanisms involved. HepG2 cells were treated at 42.5 °C for 60 min, and the post-treatment tumor supernatant (42.5Tsn) was collected. Transcriptome sequencing was performed to identify differentially expressed genes (DEGs) between the 42.5Tsn and 37Tsn treatment groups. Compared with the 37Tsn group, 446 DEGs were identified in the 42.5Tsn group. These DEGs were enriched in pathways related to DNA damage repair, cell cycle arrest, and nuclear receptor signaling. Among the 33 core genes, tumor suppressor genes (BRCA1, PALB2, SLX4) were significantly upregulated, while nuclear transcription factors that maintain stemness, such as HEY1, were significantly downregulated. Tsn induced by mild hyperthermia demonstrates the potential to promote the transition of HepG2 cells toward normal hepatocyte-like cells while suppressing their metastatic potential. However, due to the complex composition of Tsn and the transcriptome-only level of this analysis, the specific active factors, causal regulatory mechanisms, and in vivo efficacy require further validation through component analysis, functional assays, and animal models. - Source: PubMed
Publication date: 2026/06/23
Zheng LiDing YihengMa YutingLi XinhaoQi JinshengLiu JianminLi Yanning - DNA replication stress can generate mitotic defects because incompletely replicated chromosomes or unresolved replication intermediates tether sister chromatids and hinder their segregation. We and others recently uncovered a mitotic role for the oncoprotein CIP2A, which promotes chromosome stability and is essential in homologous recombination-deficient (HRD) cells. However, how CIP2A safeguards mitotic genome integrity remains unclear. Here, we investigate the role of CIP2A in mitotic responses to replication stress. We show that replication stress induces a strong increase in CIP2A foci during mitosis, highlighting its involvement in processing under-replicated DNA. In wild-type cells, CIP2A is required for efficient recruitment of the scaffold SLX4 and the nucleases MUS81 and XPF to sites of under-replicated DNA. CIP2A loss disrupts this recruitment and leads to increased anaphase lagging chromosomes and micronuclei formation. CIP2A also contributes to mitotic DNA synthesis (MiDAS), although this varies across cell lines, indicating that MiDAS and SMX complex recruitment are not strictly coupled. Together, our findings identify CIP2A as a regulator of mitotic processing of under-replicated DNA and provide a framework for understanding context-dependent vulnerabilities in cancer cells. - Source: PubMed
Publication date: 2026/05/26
Meroni AlicePellizzari AnnicaVarisco NathalieLeone FrancescoGreco GiadaHänel AndreaBrasier-Lutz PascaleWitzel IsabellSartori Alessandro AStucki Manuel