The Interplay Between the DNA Damage Response, RNA Processing and Extracellular Vesicles

Abstract

RNA processing was recently found to affect DNA damage response. The RNA processing factors THRAP3 and BCLAF1 play critical role in keeping DNA genomic stability by regulating the transcription, mRNA splicing and export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. RNA processing factors THRAP3 and BCLAF1 play critical roles in maintaining DNA genomic stability. These factors regulate transcription, mRNA splicing and nuclear RNA export of DNA repair proteins BRCA2, PALB2, Rad51, FANCD2, and FANCL in response to DNA damage. Splicing factors SRSF10 and Sam68 were found to control the DNA damage agent-induced mRNA splicing of transcripts including BCLAF1, BRCA1, BCL2L1, CASP8, CHK2, and RBBP8 to regulate apoptosis, cell-cycle transition and DNA repair. Splicing factors and RNA binding proteins (RBPs) were also found to play a critical role in DNA/RNA hybrids (R-loops) formed during transcription and RNA processing to prevent RNA-induced genome instability. At the same time, DNA repair proteins FANCI and FANCD2 were found to regulate the nuclear localization of splicing factors SF3B1 in the DNA damage response. In addition, tumor-derived extracellular vesicles (Evs) enhanced by chemotherapeutic agents in cancer were found to promote cancer metastasis and drug resistance. Inhibiting Evs from cancer cells significantly reduced cancer metastasis and drug resistance. Furthermore, cross-talk between the DNA damage response and the immune response was observed including the enhancement of the efficacy of immune checkpoint blockade by PARP inhibitors and the effect of PD-L1 on mRNA stability of various mRNAs involved in DNA damage response by acting as a novel RNA binding protein to increase drug resistance in cancer cells. This review will introduce recent progress on the interplay of the DNA damage response, the RNA processing and the extracellular vesicles mediated metastasis.

Carcinogenesis: Failure of resolution of inflammation?

“…Impaired clearance of debris fuels a pro-tumorigenic feedback loop between inflammation, DNA damage and carcinogenesis which can be aggravated by the tumor cell debris generated by cytotoxic cancer therapy including chemotherapy and radiation ( Chang et al, 2019 ; Gartung et al, 2019 ; Huang et al, 2011 ; Sulciner et al, 2018 ). Cross-talk between the cellular responses to DNA damage, RNA processing, and the extracellular vesicles mediate metastasis ( Meng, Yang, & Camp, 2019 ). Thus, differentiating between genotoxic and non-genotoxic mechanisms emphasizing the critical role of the tumor microenvironment including cancer stem cells (or tumor initiating cells), circulating tumor cells, inflammation and angiogenesis are critical for tumor initiation, tumor promotion, tumor dormancy escape and tumor progression ( Alitalo et al, 2013 ; Balkwill, Charles, & Mantovani, 2005 ; Fujiki, Sueoka, & Suganuma, 2013 ; Hanahan & Coussens, 2012 ; Hanahan & Folkman, 1996 ; Hanahan and Weinberg, 2000 , Hanahan and Weinberg, 2011 ; Trosko, 2001 ).…”

The Function and Prognostic Value of RNA-Binding Proteins in Colorectal Adenocarcinoma Were Analyzed Based on Bioinformatics of Smart Medical Big Data

“…There have been many reports on the mechanism of RBPs dysregulation affecting the key posttranscriptional steps involved in it. For example, RBP dysregulation makes it unable to combine with splicing factors to form DNA/RNA hybrids (R-loops), which play a key role in transcription and RNA processing, causing the RNA-induced genome less stable [ 9 ]. Upregulation of certain RBPs can affect their target mRNAs encode products; promote proliferation; inhibit apoptosis; and promote angiogenesis, cancer invasion, and metastasis [ 10 ].…”

BCLAF1 induces cisplatin resistance in lung cancer cells

“…These results indicated a positive association between BCLAF1 and USP22 expression. As BCLAF1 can also function as a transcriptional factor to regulate target gene expression ( 27 ), the hypothesis that BCLAF1 can directly regulate USP22 expression was considered. Supporting this, USP22 mRNA expression was found to be significantly reduced following BCLAF1 downregulation in A549/WT cells.…”

“…In addition to its role in the DNA damage response, BCLAF1 can also indirectly promote changes in cell cycle progression or the DNA damage response through transcriptional regulation ( 27 ). BCLAF1 is an essential component of a BRCA1-mRNA splicing complex ( 14 , 17 ).…”