Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex

Owen T Tuck; Benjamin A Adler; Emily G Armbruster; Arushi Lahiri; Jason J Hu; Julia Zhou; Joe Pogliano; Jennifer A Doudna

doi:10.1016/j.cell.2024.09.020

Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex

Cell. 2024 Oct 3:S0092-8674(24)01068-7. doi: 10.1016/j.cell.2024.09.020. Online ahead of print.

Authors

Owen T Tuck¹, Benjamin A Adler², Emily G Armbruster³, Arushi Lahiri⁴, Jason J Hu⁵, Julia Zhou⁴, Joe Pogliano³, Jennifer A Doudna⁶

Affiliations

¹ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
² Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA 94720, USA.
³ School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94720, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: doudna@berkeley.edu.

PMID: 39395413
DOI: 10.1016/j.cell.2024.09.020

Abstract

Hachiman is a broad-spectrum antiphage defense system of unknown function. We show here that Hachiman is a heterodimeric nuclease-helicase complex, HamAB. HamA, previously a protein of unknown function, is the effector nuclease. HamB is the sensor helicase. HamB constrains HamA activity during surveillance of intact double-stranded DNA (dsDNA). When the HamAB complex detects DNA damage, HamB helicase activity activates HamA, unleashing nuclease activity. Hachiman activation degrades all DNA in the cell, creating "phantom" cells devoid of both phage and host DNA. We demonstrate Hachiman activation in the absence of phage by treatment with DNA-damaging agents, suggesting that Hachiman responds to aberrant DNA states. Phylogenetic similarities between the Hachiman helicase and enzymes from eukaryotes and archaea suggest deep functional symmetries with other important helicases across domains of life.

Keywords: cryo-EM; genome integrity; helicase; immunity; phage defense.