Abstract
Recent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA-damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive. Here we identify two distinct mechanisms of how spliceosome U2 snRNP factors contribute to genome stability. We show that the spliceosome maintains protein levels of essential repair factors, thus contributing to homologous recombination repair. In addition, real-time laser microirradiation analysis identified rapid recruitment of the U2 snRNP factor SNRPA1 to DNA-damage sites. Functional analysis of SNRPA1 revealed a more immediate and direct role in preventing R-loop-induced DNA damage. Our present study implies a complex interrelation between transcription, mRNA splicing and the DDR. Cells require rapid spatio-temporal coordination of these chromatin transactions to cope with various forms of genotoxic stress.
Highlights
The splicing of pre-mRNA is a highly dynamic and flexible process carried out by large ribonucleoprotein complexes (RNPs), the ‘spliceosome’
Proteins of the spliceosome have been recently identified as top hits in various DNA repair screens, but their function in the DNA-damage response (DDR) still remains largely elusive. mRNA maturation, including 5′ and 3′ ends processing, splicing and transport are tightly connected with transcription
Splicing of mRNA is subject to spatio-temporal control by transcribing polymerases, chromatin remodelers and histone marks
Summary
The splicing of pre-mRNA is a highly dynamic and flexible process carried out by large ribonucleoprotein complexes (RNPs), the ‘spliceosome’. The spliceosome is stepwise assembled from the U1/U2 snRNPs, U4/U6, the U5 tri-snRNP and the Prp complex on pre-mRNA consensus sequences and performs intron excisions and exon-ligations.. Mutated components of the spliceosome were mainly detected in the U2 snRNP and U2-related proteins, which form the splicing A complex and are engaged in the initial step of splicing.. Mutated components of the spliceosome were mainly detected in the U2 snRNP and U2-related proteins, which form the splicing A complex and are engaged in the initial step of splicing.4 This surprisingly high mutation frequency strongly suggests that the compromised function of the spliceosome is an emerging hallmark of cancer and neoplastic diseases Recent whole-exome sequencing studies have detected recurrent somatic mutations in components of the spliceosome in myelodysplastic syndromes, chronic lymphocytic leukemia, pancreatic cancer, breast cancer, lung adenocarcinoma, renal clear cell carcinoma and uveal melanoma. Notably, mutated components of the spliceosome were mainly detected in the U2 snRNP and U2-related proteins, which form the splicing A complex and are engaged in the initial step of splicing. This surprisingly high mutation frequency strongly suggests that the compromised function of the spliceosome is an emerging hallmark of cancer and neoplastic diseases
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