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Título

Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability

AutorSalas-Armenteros, Irene CSIC; Barroso, Sonia CSIC ORCID; Rondón, Ana G. CSIC ORCID; Pérez-Alegre, Mónica CSIC ORCID; Andújar, Eloísa CSIC ORCID; Luna, Rosa CSIC ORCID; Aguilera, Andrés CSIC ORCID
Palabras claveGenome instability
THO complex
Alternative splicing
MFAP1/SPP381
Fecha de publicación6-ago-2019
EditorElsevier BV
CitaciónCell Reports 28: 1551-1563.e7 (2019)
ResumenTHO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing γH2AX foci and DNA breaks. This phenotype is not dependent on either transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene SPP381 cause similar transcription-independent genome instability, supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses. MFAP1 depletion affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role. THO, an mRNA biogenesis factor, interacts with MFAP1, a conserved spliceosome-associated protein. Salas-Armenteros et al. show that MFAP1/SPP381 depletion alters splicing and gene expression and increases genome instability in an RNA-DNA hybrid-independent manner. Therefore, RNA-DNA hybrid accumulation is not an intrinsic consequence of splicing defects.
Versión del editorhttp://dx.doi.org/10.1016/j.celrep.2019.07.010
URIhttp://hdl.handle.net/10261/202545
DOI10.1016/j.celrep.2019.07.010
Identificadoresdoi: 10.1016/j.celrep.2019.07.010
issn: 2211-1247
e-issn: 2211-1247
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