Genome instability is related to disease development and carcinogenesis. DNA lesions are caused
by genotoxic compounds but also by the dysregulation of fundamental processes like transcription,
DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA–DNA hybrids
(R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key
mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle
arrest and severe mitotic derangements with loss of
sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the
generation of truncated forms of the splicing factor
SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant
negative, or by gain-of-function, SRSF3-TR impair
the correct splicing and expression of the splicing
regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found
in cancer cells of different tissue origin and also in
the normal mouse liver, demonstrating a conserved
and fundamental role of SLU7 in the preservation
of genome integrity. Therefore, the dowregulation of
SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the
process of hepatocarcinogenesis