Extended Data Fig. 10: Schematic model of canonical and non-canonical ZNF695 function in L1 regulation.

This schematic, adapted from ref. ⁴⁹, illustrates ZNF695-mediated regulation of L1 retrotransposons. In normal cells, canonical KZFP transcripts encode proteins with an N-terminal KRAB domain and a C-terminal zinc finger array. The zinc finger domain binds transposable elements (TEs), while the KRAB domain recruits a heterochromatin-inducing complex—including TRIM28 (KAP1), SETDB1, the NuRD complex, HP1, and DNMTs. This complex mediates H3K9 trimethylation and directs DNMTs to methylate CpG sites in L1 promoter regions, repressing L1 retrotransposition. In tumour cells, however, non-canonical ZNF695 transcripts, lacking the zinc finger domain, predominate. This impairs TE binding and DNMT recruitment, leading to L1 promoter hypomethylation and subsequent L1 activation. Between the first and second strand synthesis by activated ORF2p (ref. ³⁸), intermediates may be cleaved and integrated into the genome. Coupled with DNA repair mechanisms, this process may generate single-base-pair indels (e.g., ID1/ID2). This suggests a dominant-negative effect, where the balance between canonical and non-canonical transcripts governs L1 methylation status.