New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. To protect genomic stability and ensure cell homeostasis, cells mount a complex signaling-based response that not only coordinates the repair of the broken DNA strand but also activates cell cycle checkpoints and, if necessary, induces cell death. The last decade has seen a flurry of studies that have identified RNA-binding proteins (RBPs) as novel regulators of the DSB response. While many of these RBPs have well-characterized roles in gene expression, it is becoming increasingly clear that they also have non-canonical functions in the DSB response that go well beyond transcription, splicing and mRNA processing. Here, we review the current understanding of how RBPs are integrated into the cellular response to DSBs and describe how these proteins directly participate in signal transduction, amplification and repair at damaged chromatin. In addition, we discuss the implications of an RBP-mediated DSB response for genome instability and age-associated diseases such as cancer and neurodegeneration.

RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs

“…Herein, we identified a novel role of the RRM-containing protein, RBM6, in regulating DSB repair, as its depletion diminishes the efficiency of HR but not NHEJ, which may explain the modest increase in γH2AX levels seen in RBM6-deficient cells. Our findings further support the emerging role of the RRM-containing protein family in orchestrating DNA repair pathways and regulating genome integrity ( 20 , 23 ). Indeed, a growing number of RRM-containing proteins have been implicated in DSB repair including hnRNP ( 94 ), RBM14 ( 95 , 96 ), NELF-E ( 9 ), FUS ( 17 , 97 ) and NONO ( 26 , 98 ).…”

In Situ Peroxidase Labeling Followed by Mass-Spectrometry Reveals TIA1 Interactome

“…Interestingly, another study utilizing a multi-bait APEX2 approach for related RBPs (FMR1, FXR1, and G3BP1) also observed enrichment in proteins associated with DNA or chromatin [ 33 ]. These interactions are perhaps reminiscent of a property shown by the RBPs fused in sarcoma (FUS) and TDP43 in promoting DNA repair by concentrating DSB signaling and repair factors [ 34 ].…”

Making Connections: Integrative Signaling Mechanisms Coordinate DNA Break Repair in Chromatin

“…Cells use multivalent binding interactions with diverse biomolecules at the DNA lesion, whose environment is within chromatin, to control molecular signals that promote detection, processing, and repair of breaks ( Figure 1 ). The various biomolecules that can be encountered at breaks include unmodified and modified nucleic acids of various structures (e.g., ssDNA and dsDNA, RNA and DNA, DNA and RNA methylation), nucleosomes (e.g., acidic patch region, core and variant histones), histone and protein modifications, as well as other DDR and chromatin factors ( Ciccia and Elledge, 2010 ; Leung et al, 2014 ; Agarwal and Miller, 2016 ; Kim et al, 2019 ; Lanz et al, 2019 ; Bader et al, 2020 ; Skrajna et al, 2020 ; Sriraman et al, 2020 ; Tan and Huen, 2020 ; Fijen and Rothenberg, 2021 ; Klaric et al, 2021 ; Lee et al, 2021 ; Par et al, 2021 ). The nucleosome, which contains 147 bp of DNA wrapped around two copies of four core histones, constitutes a repetitive structure within cells that organizes the genome, while also playing an essential role in the processing of breaks.…”

“…It is through the engagement of these multiple interactions that proteins recognize breaks within chromatin and mount a DNA damage response, which involves the transmission of signals both on chromatin and through the cell that ultimately coordinate DNA repair activities with other cellular actions (e.g., transcription, replication, and cell cycle progression). Some examples of the types of proteins that participate in the DDR include histone modifying enzymes, histone chaperones, chromatin remodelers, DNA and RNA binding and modifying enzymes, as well as DNA repair proteins themselves ( Ciccia and Elledge, 2010 ; Polo and Jackson, 2011 ; Price and D’Andrea, 2013 ; Chiu et al, 2017 ; Klaric et al, 2021 ; Par et al, 2021 ). Thus, at sites of DNA lesions, these diverse sets of factors must interact with many different biomolecules to coordinate their response both in space and in time to initiate, promote and conclude DNA damage signaling and repair activities.…”

“…The chromatin environment proximal to DSBs can also contain diverse nucleic acid structures which can serve as an interface for DDR factors; in particular, RNA:DNA hybrids (R-loops) have recently emerged as a source and consequence of DSBs ( Crossley et al, 2019 ; Marnef and Legube, 2021 ). R-loops, DNA and RNA, as well as chemically modified nucleotides, have all been shown to serve to further coordinate the recruitment and function of factors within the DDR ( Allison and Wang, 2019 ; Bader et al, 2020 ; Sriraman et al, 2020 ; Klaric et al, 2021 ; Lee et al, 2021 ; Par et al, 2021 ). Here we highlight several principal examples, illustrating how multifaceted interactions within proteins and protein complexes collaborate at DNA damage sites to coordinate the DDR and DSB repair within the chromatin environment through the engagement of diverse molecular signals.…”