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
- 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 - SLX4 is a scaffold protein pivotal in genome protection mechanisms ranging from homologous recombination and interstrand cross-link (ICL) repair to mechanisms that deal with challenged DNA replication. Many of human SLX4 functions rely on its ability to interact and control the XPF-ERCC1, MUS81-EME1, and SLX1 structure-specific endonucleases. Interaction with MUS81 relies on the conserved SAP domain of SLX4. Since the same domain in yeast Slx4 orthologs does not interact with Mus81, we investigated whether human SLX4 SAP might have retained some ancestral MUS81-independent functions. We show that human SLX4 SAP binds DNA with a preference for branched structures such as Holliday junctions. We further discovered that phosphorylation of SLX4 SAP by CDK1, which promotes interaction with MUS81, inhibits DNA binding. We identified separation of function mutants that impair either DNA or MUS81 binding. Binding to MUS81 is required in response to ICL-inducing agents, methyl methanesulfonate (MMS), TOP1, and PARP inhibition. Instead, DNA binding is required in response to ICL-inducing agents and MMS but not after TOP1 or PARP inhibition. Our work indicates that phosphorylation by CDK1 acts as a regulatory switch between DNA binding and MUS81-dependent functions of SLX4, to accommodate specific DNA lesions or secondary structures. - Source: PubMed
Scaglione SarahGaillard Pierre-Henri - : Most patients with hepatocellular carcinoma (HCC) present with advanced disease and have limited systemic treatment options. Oxaliplatin shows clinical activity in HCC but its effectiveness is frequently curtailed by intrinsic and acquired resistance. We sought to systematically identify genetic vulnerabilities that increase oxaliplatin sensitivity in HCC. : Genome-scale negative-selection CRISPR-Cas9 screens were conducted in two genetically distinct HCC cell lines (Hep3B and MHCC-97H) under low-dose oxaliplatin to discover conserved determinants of sensitivity. Selected DNA damage response (DDR) hits were validated. An oxaliplatin-resistant MHCC-97H subline was generated for transcriptomic profiling to characterize resistance-associated programs. Screen results were integrated with TCGA-LIHC expression and survival data to evaluate clinical relevance. Additionally, we analyzed bulk RNA-seq data from biopsy specimens collected from 36 HCC patients prior to initiation of hepatic arterial infusion chemotherapy (HAIC), comparing expression levels of the DDR genes between patients with objective response and non-responders. : Screens in both cell lines converged on DDR pathways, particularly nucleotide excision repair (NER) and the Fanconi anemia/interstrand crosslink repair network; shared sensitizers included (), and . Validation experiments showed that disruption of representative DDR factors ( and ) synergistically increased oxaliplatin efficacy at concentrations as low as 0.5 μM. Transcriptomic analysis of the resistant MHCC-97H subline revealed coordinated upregulation of DNA repair programs, G2/M checkpoint and E2F target signatures, and epithelial-mesenchymal transition features. Integration with TCGA-LIHC data demonstrated frequent overexpression of many screen-identified DDR genes in primary HCC and an association between higher expression of selected factors and poorer patient survival. In the HAIC cohort, several DDR genes, including , , , , , , , and , were significantly lower in the objective response group. : DDR components represent candidate biomarkers and therapeutic targets whose inhibition may enhance oxaliplatin efficacy in HCC. - Source: PubMed
Publication date: 2026/04/24
Ouyang HanyueHuang DiyunWen DongshengHuang LichangWu ZichaoLai ZhichengHe MinkeWu WenchaoShi Ming - Olaparib is registered for use in ovarian, breast, pancreatic and prostate cancers with a BRCA1/2 mutation and/or mutations in other homologous recombination deficiency (HRD) genes. HRD gene mutations are also found in other cancer types, and these cancers may also benefit from olaparib therapy. We aimed to evaluate the efficacy of olaparib in advanced cancers harboring a (likely) pathogenic germline or somatic mutation in a gene involved in homologous recombination (HR). - Source: PubMed
Publication date: 2026/05/08
Joris SDenys HCollignon JRasschaert Mde Roodenbeke D TDuhoux F PCanon J LTejpar SMebis JDecoster LAftimos PDe Grève J - Crossover (CO) formation between homologous chromosomes is essential for genetic diversity and accurate meiotic chromosome segregation. This process involves two key steps: the designation of a subset of meiotic double-strand breaks to CO-designated sites and subsequent CO resolution by Holliday junction (HJ) resolvase. However, how these steps are functionally coupled remains elusive. Here, we showed that COSA-1, essential for CO designation, directly interacts with the SLX-4 scaffold protein, which organizes the SLX-1, XPF-1, and MUS-81 HJ resolvases. Disrupting this interaction results in persistent unrepaired recombination intermediates and defective CO formation. Notably, these defects can be largely rescued by the artificial tethering of SLX-4 to the CO designation proteins. We further demonstrate that COSA-1 promotes assembly of the SLX-4 resolvase complex and provide evidence that this mechanism coupling CO designation with resolution is evolutionarily conserved. Together, our findings support a model in which CO designation proteins ensure accurate CO formation by directly recruiting the resolution machinery. - Source: PubMed
Publication date: 2026/04/24
Liu GuotengYang YuejunNan WencongXiao TongxinGuo ZongyuZhang MeiyuWang YuchenWu XuezhenGartner AntonZhang HongtaoHong Ye