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Clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonucleases have revolutionized biotechnology for their potential as programmable genome editors. Yet, most natural nucleases and their variants have limitations. Here, we report a fully synthetic CRISPR-associated (Cas) nuclease (α-synCas) designed by Ancestral Sequence Reconstruction (ASR) that displays a set of robust and distinct targeting properties, not found in any other known CRISPR-Cas Class 2 system. We show that α-synCas is a PAMless nuclease able to catalyse RNA-guided, specific cleavage of dsDNA, ssDNA and ssRNA. The synthetic enzyme is also capable of sequence-nonspecific degradation of dsDNA, ssDNA and ssRNA following activation by complementary dsDNA, ssDNA and ssRNA targets. Furthermore, α-synCas exhibits a robust genome editing activity in human cells and bacteria. Cryo-electron microscopy structures of α-synCas ternary and quaternary complexes provide a framework to understand the structural basis for its expanded enzymatic activities. The capability for programmable multimodal targeting of virtually any nucleic acid sequence distinguishes α-synCas as a promising new tool to extend current CRISPR-based technologies.