C. elegans THSC complex deficiency leads to replication stress and genome instability

Abstract

The THSC/TREX-2 complex is conserved from yeast to humans and is involved in mRNP biogenesis. Defects in the coupling of transcription with mRNA processing and export results in DNA damage and genome instability from yeast to human cells. Notably, the genetic instability and transcriptional defects observed in yeast THSC mutants is due to R-loops accumulation as co-transcriptional cleavage of the transcript reduced to some extend both defects. However, recently our laboratory has show that depletion of human counterpart, despite increasing genomic instability, does not lead to an obvious accumulation of R-loops. Nevertheless, we decide to use the simple metazoan Caernorhabditis elegans to further address this unexpected data. Through the characterization of two putative members of the C. elegans THSC complex we have observed that lack of the THSC/TREX-2 THP-1 leads to, DNA damage accumulation and replication defects at the germline. Importantly, microinjection of RNase H, that removes R-loops, partially restores the Cy3-dUTP incorporation in the nematode germline consistent with R-loops interfering with replication progression. This research provides new insight into the THSC/TREX-2 complex contribution to the maintenance of genome integrity in multicellular organisms.