ZTF-8 Interacts with the 9-1-1 Complex and Is Required for DNA Damage Response and Double-Strand Break Repair in the C. elegans Germline

Germline mutations in dna repair genes are linked to tumor progression. furthermore,failure in either activating a dna damage checkpoint or repairing programmed meiotic double-strand breaks (dsbs) can impair chromosome segregation. therefore,understanding the molecular basis for dna damage response (ddr) and dsb repair (dsbr) within the germline is highly important. here we define ztf-8,a previously uncharacterized protein conserved from worms to humans,as a novel factor involved in the repair of both mitotic and meiotic dsbs as well as in meiotic dna damage checkpoint activation in the c. elegans germline. ztf-8 mutants exhibit specific sensitivity to γ-irradiation and hydroxyurea,mitotic nuclear arrest at s-phase accompanied by activation of the atl-1 and chk-1 dna damage checkpoint kinases,as well as accumulation of both mitotic and meiotic recombination intermediates,indicating that ztf-8 functions in dsbr. however,impaired meiotic dsbr progression partially fails to trigger the cep-1/p53-dependent dna damage checkpoint in late pachytene,also supporting a role for ztf-8 in meiotic ddr. ztf-8 partially co-localizes with the 9-1-1 ddr complex and interacts with mrt-2/rad1,a component of this complex. the human rhino protein rescues the phenotypes observed in ztf-8 mutants,suggesting functional conservation across species. we propose that ztf-8 is involved in promoting repair at stalled replication forks and meiotic dsbs by transducing dna damage checkpoint signaling via the 9-1-1 pathway. our findings define a conserved function for ztf-8/rhino in promoting genomic stability in the germline. © 2014 kim,colaiácovo.