CONICET | Buscador de Institutos y Recursos Humanos

INVESTIGADORES

SCHOR Ignacio Esteban

datos académicos

artículos

capítulos de libros

congresos y reuniones científicas

Título:

Genomics data integration reveals a role of intron architecture in the alternative splicing response to DNA damage

Autor/es:

IGNACIO E. SCHOR; MANUEL MUÑOZ

Lugar:

Buenos Aires

Reunión:

Congreso; JOINT MEETING OF BIOSCIENCE SOCIETIES - LIII ANNUAL MEETING OF ARGENTINE SOCIETY OF BIOCHEMISTRY AND MOLECULAR BIOLOGY (SAIB); 2017

Institución organizadora:

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular y otras 9 sociedades nacionales de biociencias

Resumen:

DNA damage caused by conditions such us UVirradiation affects gene expression patterns by different mechanisms, also includingswitching between isoforms of the same genes by means of alternative splicing(AS) regulation. Previous work uncovered a pathway that modulate AS patterns inUV-treated human keratynocites, involving the generation of pyrimidine dimers,the kinase ATR and the phosphorylation of RNA pol II, a major mediator of theresponse. Here we analyze alternative splicing regulation in response to DNAdamage genome wide, integrating transcriptomics, proteomics and RNA bindingprotein target scanning. We have taken advantage of globalcharacterization of AS patterns through RNA-seq in three conditions: untreatedcells, UV-treated and UV-treated reverted by photolyase-mediated repair ofdamaged DNA. Analysis of the general architecture of the gene suggested thatthe length of the flanking introns is well correlated with the direction of theAS effect: exon cassettes showing higher inclusion after DNA-damage haveshorter introns than expected, while those showing lower inclusion have longerintrons. Hypothesis testing using a logistic regression model confirmed theinfluence of intron length and highlighted differences between both modes ofregulation: only upstream intron was important for exon up-regulation, whileboth flanking introns influenced exon down-regulation. Our working model isthat up-regulation is mainly mediated by a phosporylation-induced change in RNApol II elongation rate, as previously reported, while down-regulation isrelated to splicing regulators binding both flanking introns. Target scanningrevealed that indeed longer introns tend to have a higher ratio betweennegative (hnRNP proteins) and positive (SR proteins) regulators. Finally, quantificationof protein abundance in normal vs. UV-treated cells confirmed that hnRNPproteins but not SR proteins increase their abundance in this condition,further supporting our model.

enviar mensaje