Beyond the Trinity of ATM, ATR, and DNA-PK: Multiple Kinases Shape the DNA Damage Response in Concert With RNA Metabolism

Abstract

Our genome is constantly exposed to endogenous and exogenous sources of DNA damage resulting in various alterations of the genetic code. DNA double-strand breaks (DSBs) are considered one of the most cytotoxic lesions. Several types of repair pathways act to repair DNA damage and maintain genome stability. In the canonical DNA damage response (DDR) DSBs are recognized by the sensing kinases Ataxia-telangiectasia mutated (ATM), Ataxia-telangiectasia and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK), which initiate a cascade of kinase-dependent amplification steps known as DSB signaling. Recent evidence suggests that efficient recognition and repair of DSBs relies on the transcription and processing of non-coding (nc)RNA molecules by RNA polymerase II (RNAPII) and the RNA interference (RNAi) factors Drosha and Dicer. Multiple kinases influence the phosphorylation status of both the RNAPII carboxy-terminal domain (CTD) and Dicer in order to regulate RNA-dependent DSBs repair. The importance of kinase signaling and RNA processing in the DDR is highlighted by the regulation of p53-binding protein (53BP1), a key regulator of DSB repair pathway choice between homologous recombination (HR) and non-homologous end joining (NHEJ). Additionally, emerging evidence suggests that RNA metabolic enzymes also play a role in the repair of other types of DNA damage, including the DDR to ultraviolet radiation (UVR). RNAi factors are also substrates for mitogen-activated protein kinase (MAPK) signaling and mediate the turnover of ncRNA during nucleotide excision repair (NER) in response to UVR. Here, we review kinase-dependent phosphorylation events on RNAPII, Drosha and Dicer, and 53BP1 that modulate the key steps of the DDR to DSBs and UVR, suggesting an intimate link between the DDR and RNA metabolism.

Proteome analysis of Saccharomyces cerevisiae after methyl methane sulfonate (MMS) treatment

“…Although many of the proteins that comprise the initial response to MMS have been identified but, the complete repertoire of downstream DDR events induced by MMS especially with respect to the RNAPII remains poorly understood [ [12] , [13] , [14] , [15] , 54 ]. Comparison of fractions associated with RNAP-II in MMS treated sample indicate proteins that are differentially regulated and have a greater degree of association with RNAP-II in response to the MMS during active transcription.…”

DE NOVOSEQUENCING AND ANALYSIS OF THERANA CHENSINENSISTRANSCRIPTOME TO DISCOVER PUTATIVE GENES ASSOCIATED WITH POLYUNSATURATED FATTY ACIDS

“…The data were analyzed on the free online platform of Majorbio I-Sanger Cloud Platform (www.i-sanger.com). De novo transcriptome assembly was carried out using the Trinity software (https://github.com/trinityrnaseq/trinityrnaseq) [1].…”

Jack of all trades? The versatility of RNA in DNA double-strand break repair

“…For example, Dicer and Drosha binding partners can be regulated by ATM [ 20–23 ], ATM can regulate miRNA transcription by phosphorylating transcription factors, and regulate miRNA maturation, processing, and export from the nucleus [ 24 ]. Furthermore, DGCR8 can be phosphorylated by c-Abl kinase upon DSB induction [ 25 , 26 ], BRCA1 can associate with Drosha [ 27 ] and bind to pri-miRNAs [ 20 , 28 ], and DSBs can induce p53-mediated miRNA transcriptional changes, resulting in differential expression of miRNAs [ 28 ]. Over 60% of protein-coding mRNAs are predicted to be targeted by miRNAs [ 20 ], and one miRNA can target many different genes [ 29 ].…”