MDC1 maintains active elongation complexes of RNA polymerase II.

The role of MDC1 in the DNA damage response has been extensively studied; however, its impact on other cellular processes is not well understood. Here, we describe the role of MDC1 in transcription as a regulator of RNA polymerase II (RNAPII). Depletion of MDC1 causes a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein-encoding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to changes in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment.

Differential protein occupancy profiling of the mRNA transcriptome.

BACKGROUND: RNA-binding proteins (RBPs) mediate mRNA biogenesis, translation and decay. We recently developed an approach to profile transcriptome-wide RBP contacts on polyadenylated transcripts by next-generation sequencing. A comparison of such profiles from different biological conditions has the power to unravel dynamic changes in protein-contacted cis-regulatory mRNA regions without a priori knowledge of the regulatory protein component. RESULTS: We compared protein occupancy profiles of polyadenylated transcripts in MCF7 and HEK293 cells. Briefly, we developed a bioinformatics workflow to identify differential crosslinking sites in cDNA reads of 4-thiouridine crosslinked polyadenylated RNA samples. We identified 30,000 differential crosslinking sites between MCF7 and HEK293 cells at an estimated false discovery rate of 10%. 73% of all reported differential protein-RNA contact sites cannot be explained by local changes in exon usage as indicated by complementary RNA-seq data. The majority of differentially crosslinked positions are located in 3' UTRs, show distinct secondary-structure characteristics and overlap with binding sites of known RBPs, such as ELAVL1. Importantly, mRNA transcripts with the most significant occupancy changes show elongated mRNA half-lives in MCF7 cells. CONCLUSIONS: We present a global comparison of protein occupancy profiles from different cell types, and provide evidence for altered mRNA metabolism as a result of differential protein-RNA contacts. Additionally, we introduce POPPI, a bioinformatics workflow for the analysis of protein occupancy profiling experiments. Our work demonstrates the value of protein occupancy profiling for assessing cis-regulatory RNA sequence space and its dynamics in growth, development and disease.

[Cancer in esophagus and cardia--incidence trends in Denmark]. / Kraeft i øsofagus og cardia--incidensudvikling i Danmark.

INTRODUCTION: The incidence of adenocarcinoma in esophagus and cardia has been reported as increasing in a number of countries over recent decades. We examined if a similar increase has occurred in Denmark. The study evaluates the incidence trends for esophagus- and stomach cancer in the period 1943-2003 with focus on changes since 1978. MATERIALS AND METHODS: All data were retrieved from the Danish Cancer Register, which contains information on cancer cases in Denmark since 1943, including detailed information about histology since 1978. Age-standardized incidence rates were calculated based on the age distribution in the World Standard Population (WSP) and the Danish population in 2000 (DK-2000). RESULTS: The age-standardized (DK-2000) incidence rates for esophagus cancer in Denmark were stable in the period 1943-1977, but then increased from 3.7 per 100,000 in the period 1978-1982 to 6.8 per 100,000 in the period 1998-2003. The corresponding incidence rate for stomach cancer decreased over the entire study period from 21.9 per 100,000 in 1943-1947 to 9.7 per 100,000 in 1998-2003. The increased incidence of esophagus cancer in the period from 1978 was mainly due to an increase in the incidence of adenocarcinomas, particularly among men. During the period 1978-2003 we observed a marked decrease in the incidence of adenocarcinoma in the distal stomach, whereas the incidence of adenocarcinoma in the cardia was constant in this period. CONCLUSION: The incidence of esophageal adenocarcinoma has increased during the past 25 years in Denmark, whereas the incidence of adenocarcinoma in the cardia has remained constant.