ZNF280A

ZNF280A is a chromatin-associated zinc finger protein that functions in DNA double-strand break (DSB) repair and transcriptional regulation. At DSB sites, ZNF280A promotes long-range DNA-end resection by recruiting the BLM-DNA2 helicase-nuclease complex and enhancing its enzymatic activity, thereby enabling homologous recombination repair (PMID:40523937). ZNF280A also acts as a transcriptional co-regulator: it interacts with the transcription factor CUX2 to drive ACRV1 promoter activation and PI3K/AKT-dependent glycolytic reprogramming (PMID:41338461), upregulates EIF3C to promote lung adenocarcinoma cell proliferation (PMID:33414445), stabilizes RPS14 protein by suppressing its ubiquitin-dependent degradation to sustain PI3K-AKT signaling in colorectal cancer (PMID:36059657), and inactivates the Hippo signaling pathway to promote colorectal cancer cell cycle progression (PMID:30847384).

1. 2019 Medium

   The first functional characterization of ZNF280A established that it promotes cell proliferation in colorectal cancer by inactivating the Hippo signaling pathway, revealing it as a pro-proliferative factor linked to a defined developmental signaling cascade.

   Evidence siRNA knockdown, Hippo pathway luciferase reporter, Western blot, xenograft assays in CRC cells

   PMID:30847384

   Open questions at the time

   • Mechanism by which ZNF280A inactivates Hippo signaling is undefined
   • Direct binding to Hippo pathway components not tested
   • Single-lab observation in one cancer type
2. 2021 Medium

   Epistasis experiments placed EIF3C as a functional mediator downstream of ZNF280A in lung adenocarcinoma, suggesting ZNF280A acts as a transcriptional regulator controlling translation machinery components.

   Evidence ZNF280A overexpression and EIF3C knockdown rescue, gene expression profiling, in vitro and in vivo assays in LUAD cells

   PMID:33414445

   Open questions at the time

   • Whether ZNF280A directly binds the EIF3C promoter is not determined
   • Biochemical mechanism linking ZNF280A to EIF3C transcription is missing
   • Specificity of ZNF280A transcriptional targets not addressed genome-wide
3. 2022 Medium

   ZNF280A was shown to stabilize RPS14 protein by preventing its ubiquitin-dependent proteasomal degradation, connecting ZNF280A to post-translational protein quality control and PI3K-AKT pathway activation in colorectal cancer.

   Evidence shRNA knockdown, ubiquitination assay, Western blot for RPS14 levels, functional assays in CRC cells

   PMID:36059657

   Open questions at the time

   • The E3 ubiquitin ligase responsible for RPS14 ubiquitination is not identified
   • Whether ZNF280A acts directly on ubiquitination machinery or indirectly through transcriptional regulation is unknown
   • Single-lab finding in CRC
4. 2025 High

   A genome-wide screen identified ZNF280A as a DSB-recruited factor that promotes long-range DNA-end resection through recruitment and activation of the BLM-DNA2 complex, establishing its primary molecular function in homologous recombination repair and linking its loss to the 22q11.2 distal deletion syndrome.

   Evidence High-throughput microscopy cDNA screen (chromORFeome), loss-of-function/epistasis with BLM-DNA2, functional rescue in patient-derived cells, multiple orthogonal assays

   PMID:40523937

   Open questions at the time

   • Structural basis of ZNF280A interaction with BLM-DNA2 is not resolved
   • Whether ZNF280A zinc fingers directly engage DNA or protein interfaces at break sites is unknown
   • Contribution of ZNF280A loss to the clinical phenotype of 22q11.2 distal deletion syndrome beyond cellular DNA repair defects is not established
5. 2025 Medium

   ZNF280A was shown to physically interact with the transcription factor CUX2 and facilitate its recruitment to the ACRV1 promoter, providing the first direct evidence of ZNF280A acting as a transcriptional co-activator at a specific genomic locus and linking this to PI3K/AKT-driven glycolytic reprogramming.

   Evidence Reciprocal co-immunoprecipitation of ZNF280A-CUX2, chromatin recruitment assay at ACRV1 promoter, AKT inhibition, glycolysis measurements in ovarian cancer cells

   PMID:41338461

   Open questions at the time

   • Whether ZNF280A-CUX2 co-regulation extends beyond ACRV1 to other loci is unknown
   • DNA-binding specificity of ZNF280A itself has not been characterized
   • Relationship between ZNF280A's DNA repair and transcriptional functions is unexplored

• How ZNF280A coordinates its dual roles in DSB repair (BLM-DNA2 recruitment) and transcriptional regulation (CUX2 co-activation, EIF3C/RPS14 control) remains unresolved, and no structural or genome-wide binding data define its DNA recognition specificity or full target repertoire.
• No ChIP-seq or structural data for ZNF280A DNA-binding specificity
• Separation-of-function between DNA repair and transcriptional roles not tested
• No interactome study beyond BLM-DNA2 and CUX2