In order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression, and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage- and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation. Indeed, we describe how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events but increases the sensitivity to DNA damaging agents if the expression is maintained long-term.

In order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage-and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation.Indeed, we described how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events, but increases the sensitivity to DNA damaging agents if the expression is maintained long-term. Prados-Carvajal et al

Squamous cell lung cancer and adenocarcinoma are the most common subtypes of the lung tumours. The search for cancer-directed treatments has increased the need for understanding molecular features of either histological subtypes. The aim of this study was to identify the transcriptional regulation differences due to miRNA expression profiles between SCC and adenocarcinoma. In this work, a total of 44 patients were evaluated to assess the correlation between the miRNA and messenger RNA expression levels. We detected changes in 56 mRNAs as well as in 9 miRNAs between SCC and adenocarcinoma. Nearly 20% of overall deregulated genes were targeted by at least one of the 9 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a, miR-483-5p, miR-494, miR-601 and miR-708) differentially expressed between SCC and adenocarcinoma (table 1). Genes predicted (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) to be targeted by several miRNAs were individually validated by qRT-PCR. We found genes involved in tight junctions and others involved in resistance to anticancer agents. These genes were reliable biomarkers to detect differences between the two most common histological subtypes of lung cancer. Therefore, transcriptional regulation differences through miRNA expression play an important role in key hallmarks of non-small cell lung cancer. Citation Format: Sonia Molina-Pinelo, Gabriel Gutierrez-Pozo, Maria D. Pastor, Marta Hergueta, Gema Moreno-Bueno, Rocio Garcia-Carbonero, Ana BS Nogal, Rocio Suarez, Ana Salinas, Francisco Pozo-Rodríguez, Fernando Lopez-Rios, Teresa Agulló-Ortuño, Jose Palacios, Amancio Carnero, Luis G. Paz-Ares. Transcriptionalregulation by microRNAs in NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5305. doi:10.1158/1538-7445.AM2013-5305