Abstract
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.
Highlights
Genome instability is a hallmark of cancer cells and a critical feature that enables tumor progression
We propose that ZTF-8 is involved in promoting repair at blocked replication fork sites and meiotic double-strand breaks (DSBs) in part by transducing DNA damage checkpoint signaling via the 9-1-1 DNA damage response complex
While the S-phase checkpoint is intact, impaired meiotic double-strand break repair (DSBR) progression partially fails to trigger the CEP-1/p53dependent DNA damage checkpoint in late pachytene, suggesting a role for ZTF-8 in DNA damage response (DDR). This is further supported by the interaction of ZTF-8 with MRT-2, the C. elegans homolog of the Rad1 protein found in S. pombe, Drosophila, and mammals, and a member of the 9-1-1 DDR complex, and the impaired localization of HUS-1 onto chromatin in response to exogenous DSB formation in ztf-8 mutants
Summary
Genome instability is a hallmark of cancer cells and a critical feature that enables tumor progression. Instability allows cells to break and reform chromosomes, generate new oncogene fusions, inactivate tumor suppressor genes, amplify drug resistance genes, and increase their malignancy. This whole progression often accompanies the disruption of DNA repair genes as the failure in DNA repair permits an increased rate of chromosome breakage and mutagenesis [1]. Many mutations involved in DNA repair genes have been linked to the progression of diverse cancers including breast, ovarian, and skin cancer, as well as leukemia and lymphomas. Considering that many germline mutations in DNA repair genes involved in double-strand break repair (DSBR) are linked to tumor progression [2], and that failure to properly repair programmed meiotic DSBs can impair chromosome segregation, understanding DSBR at a molecular and cellular level, in a genetically tractable multicellular system, is of extreme importance
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