Structure of SALL4 zinc-finger domain reveals link between AT-rich DNA binding and Okihiro syndrome

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Abstract / Description of output

Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for thedevelopment of multiple organs, including limbs. Mutations in SALL4 are associated with Okihirosyndrome and SALL4 is also a known target of thalidomide. SALL4 protein has a distinct preference forAT-rich sequences, recognised by a pair of zinc fingers at the C-terminus. However, unlike manycharacterised zinc finger proteins, SALL4 shows flexible recognition with many different combinationsof AT-rich sequences being targeted. SALL4 interacts with the NuRD corepressor complex whichpotentially mediates repression of AT-rich genes. We present a crystal structure of SALL4 C-terminalzinc fingers with an AT-rich DNA sequence, which shows that SALL4 uses small hydrophobic and polarside chains to provide flexible recognition in the major groove. Missense mutations reported inpatients that lie within the C-terminal zinc fingers reduced overall binding to DNA but not thepreference for AT-rich sequences. Furthermore, these mutations altered association of SALL4 with ATrichgenomic sites, providing evidence that these mutations are likely pathogenic.
Original languageEnglish
Article numbere202201588
Number of pages13
JournalLife Science Alliance
Issue number3
Early online date12 Jan 2023
Publication statusPublished - Mar 2023


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