ZNF280C

ZNF280C (ZPET) is a C2H2 zinc finger protein operating at the interface of the DNA damage response and chromatin-based gene repression (PMID:30567999, PMID:35605119). As a single-stranded DNA-binding protein, it localizes to double-strand breaks and stalled replication forks, where it blocks MRE11 association with ssDNA to slow DNA end resection independently of 53BP1 and HELB, thereby acting as a repressor of homologous recombination; its loss elevates HR, accelerates forks under replication stress, and confers resistance to DSB-inducing agents and PARP inhibition (PMID:30567999). In a parallel chromatin role, ZNF280C occupies H3K27me3-marked loci, co-localizes with and counteracts CTCF/cohesin to condense chromatin at tumor suppressor cis-elements, and recruits SMCHD1 to sustain focal and broad H3K27me3, promoting colorectal tumorigenesis (PMID:35605119). Beyond these two arms, no unifying mechanism connecting its resection-control and transcriptional-repression activities has been characterized in the available corpus.

1. 2018 High

   Established ZNF280C as a direct biochemical regulator of DNA end resection, answering how an ssDNA-binding factor restrains the nuclease step of repair.

   Evidence BioID proximity proteomics, in vitro ssDNA-binding and MRE11-inhibition assays, chromatin fractionation in depleted cells

   PMID:30567999

   Open questions at the time

   • Does not define how ZPET is recruited to or removed from breaks
   • Structural basis of ssDNA binding and MRE11 competition unresolved
2. 2018 High

   Defined the cellular consequence of ZNF280C activity by showing its loss enhances HR and alters fork dynamics, framing it as an HR repressor with therapeutic relevance to PARP inhibition.

   Evidence Loss-of-function with HR assay, DNA fiber assay, clonogenic survival after DSB agents and PARPi

   PMID:30567999

   Open questions at the time

   • Does not address pathway choice regulation at the chromatin level
   • Relationship to other resection antagonists not delineated
3. 2022 High

   Revealed a distinct transcriptional/epigenetic function, showing ZNF280C maintains H3K27me3-dependent silencing by opposing CTCF/cohesin and recruiting SMCHD1 at tumor suppressor loci.

   Evidence ChIP-seq, ATAC-seq, CRISPRi/RNAi with H3K27me3 quantification, Co-IP, xenograft and colorectal tumorigenesis models

   PMID:35605119

   Open questions at the time

   • Mechanism linking DNA-binding to chromatin condensation unclear
   • Whether DSB and chromatin-repression roles are coupled is unknown
4. 2026 Medium

   Identified a new physical partner (KMT5C) and a non-canonical chromatin context, raising the possibility that ZNF280C directs H4K20me3 deposition outside classical heterochromatin.

   Evidence Co-IP/pulldown and ChIP-seq co-localization at H3K9me3-/H4K20me3+ sites (preprint)

   PMID:42182233

   Open questions at the time

   • Single preprint, not peer-reviewed
   • Functional consequence of KMT5C recruitment not tested
   • Reciprocal interaction validation lacking

• Whether the resection-control and chromatin-repression functions of ZNF280C reflect one integrated mechanism or two separable activities remains unresolved.
• No structural model of ZNF280C
• No unifying model connecting DSB and transcriptional roles
• Domain requirements for each function undefined