scholarly journals The roles of RNA in DNA double-strand break repair

2020 ◽  
Vol 122 (5) ◽  
pp. 613-623 ◽  
Author(s):  
Aldo S. Bader ◽  
Ben R. Hawley ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Genome Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Strand Break ◽  
Rna Molecules ◽  
Repair Mechanisms ◽  
Recent Developments

AbstractEffective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for carcinogenesis. Multiple pathways have evolved to protect against both intrinsic and extrinsic genotoxic events, and recent developments have highlighted an unforeseen critical role for RNA in ensuring genome stability. It is currently unclear exactly how RNA molecules participate in the repair pathways, although many models have been proposed and it is possible that RNA acts in diverse ways to facilitate DNA repair. A number of well-documented DNA repair factors have been described to have RNA-binding capacities and, moreover, screens investigating DNA-damage repair mechanisms have identified RNA-binding proteins as a major group of novel factors involved in DNA repair. In this review, we integrate some of these datasets to identify commonalities that might highlight novel and interesting factors for future investigations. This emerging role for RNA opens up a new dimension in the field of DNA repair; we discuss its impact on our current understanding of DNA repair processes and consider how it might influence cancer progression.

scholarly journals The emerging role of RNAs in DNA damage repair

2017 ◽  
Vol 24 (4) ◽  
pp. 580-587 ◽  
Author(s):  
Ben R Hawley ◽  
Wei-Ting Lu ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Repair Process ◽  
Rna Molecules ◽  
Processing Enzymes ◽  
Damage Repair ◽  
New Findings ◽  
Integral Role ◽  
Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

scholarly journals Take a Break to Repair: A Dip in the World of Double-Strand Break Repair Mechanisms Pointing the Gaze on Archaea

2021 ◽  
Vol 22 (24) ◽  
pp. 13296
Author(s):  
Mariarosaria De Falco ◽  
Mariarita De Felice
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Genome Stability ◽  
Developmental Disorders ◽  
Strand Break ◽  
Human Diseases ◽  
Dna Damages ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Repair Pathways

All organisms have evolved many DNA repair pathways to counteract the different types of DNA damages. The detection of DNA damage leads to distinct cellular responses that bring about cell cycle arrest and the induction of DNA repair mechanisms. In particular, DNA double-strand breaks (DSBs) are extremely toxic for cell survival, that is why cells use specific mechanisms of DNA repair in order to maintain genome stability. The choice among the repair pathways is mainly linked to the cell cycle phases. Indeed, if it occurs in an inappropriate cellular context, it may cause genome rearrangements, giving rise to many types of human diseases, from developmental disorders to cancer. Here, we analyze the most recent remarks about the main pathways of DSB repair with the focus on homologous recombination. A thorough knowledge in DNA repair mechanisms is pivotal for identifying the most accurate treatments in human diseases.

scholarly journals Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons

Science ◽  
2021 ◽  
Vol 372 (6537) ◽  
pp. 91-94
Author(s):  
Dylan A. Reid ◽  
Patrick J. Reed ◽  
Johannes C. M. Schlachetzki ◽  
Ioana I. Nitulescu ◽  
Grace Chou ◽  
...  
Keyword(s):  
Dna Repair ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genome Instability ◽  
Human Life ◽  
Embryonic Stem ◽  
Histone H2a ◽  
Human Neurons ◽  
Repair Mechanisms ◽  
Induced Neurons

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

How to find small non-coding RNAs in bacteria

2005 ◽  
Vol 386 (12) ◽  
pp. 1219-1238 ◽  
Author(s):  
Jörg Vogel ◽  
Cynthia Mira Sharma
Keyword(s):  
Small Rnas ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Rna Molecules ◽  
Regulatory Circuit ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Response To Stress ◽  
Non Coding Rnas

AbstractSmall non-coding RNAs (sRNAs) have attracted considerable attention as an emerging class of gene expression regulators. In bacteria, a few regulatory RNA molecules have long been known, but the extent of their role in the cell was not fully appreciated until the recent discovery of hundreds of potential sRNA genes in the bacteriumEscherichia coli. Orthologs of theseE. colisRNA genes, as well as unrelated sRNAs, were also found in other bacteria. Here we review the disparate experimental approaches used over the years to identify sRNA molecules and their genes in prokaryotes. These include genome-wide searches based on the biocomputational prediction of non-coding RNA genes, global detection of non-coding transcripts using microarrays, and shotgun cloning of small RNAs (RNomics). Other sRNAs were found by either co-purification with RNA-binding proteins, such as Hfq or CsrA/RsmA, or classical cloning of abundant small RNAs after size fractionation in polyacrylamide gels. In addition, bacterial genetics offers powerful tools that aid in the search for sRNAs that may play a critical role in the regulatory circuit of interest, for example, the response to stress or the adaptation to a change in nutrient availability. Many of the techniques discussed here have also been successfully applied to the discovery of eukaryotic and archaeal sRNAs.

scholarly journals Delineating the Role of Interplay between m6A Machinery Genes and IGF2BP Group of RNA-Binding Proteins in B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4472-4472
Author(s):  
Sumedha Saluja ◽  
Jay Singh ◽  
Ayushi Jain ◽  
Shilpi Chaudhary ◽  
Karthikeyan Pethusamy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Cancer Progression ◽  
Rna Binding ◽  
Conflicts Of Interest ◽  
Rna Binding Proteins ◽  
Colorimetric Assay ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cell Renewal

Abstract Introduction: N-6-methyladenosine (m6A) is the most common, dynamic and reversible RNA modification with implications in various cancers including leukemia. Deregulation of m6A writer METTL3 has been shown to promote disease progression in various cancers, including Acute Myeloid Leukemia(AML). Overexpression of METTL3 led to increase in cell growth and inhibition of apoptosis, thereby promoting leukemia progression. Interestingly, m6A demethylases (erasers) ALKBH5 and FTO have also seen to play a critical role in progression of AML by mediating cancer stem cell renewal. The IGF2BP family of RNA binding, oncofetal proteins have recently been identified as m6A readers and have also been shown to be deregulated in B-ALL. In this work, we have studied the expression of m6A machinery (writers, erasers and readers) in primary (naïve and relapsed) B-ALL patient samples. The percentage of methylated RNA (m6A%) was also evaluated in B-ALL patient samples. Materials and Methods: 91 newly diagnosed (naïve) and 47 relapsed B-ALL pediatric patient bone marrow samples were collected from BRAIRCH, AIIMS, New Delhi. Gene expression of m6A writer (METTL3), readers (IGF2BP1/3) and erasers (ALKBH5, FTO) was studied by RT-qPCR. Peripheral blood (PB) of 20 healthy individuals and 18 uninvolved bone marrow (BM) samples of patients with other malignancies were used as controls. m6A% was also measured in B-ALL patients (naïve n=47, relapsed n=43,) and controls (PB n=20, BM n=16, CD34+ cells from normal donors n=5) by an anti-m6A based colorimetric assay. Results: The ratio of m6A writer METTL3 to m6A eraser ALKBH5 was significantly higher in the naïve and relapsed B-ALL patients as compared to all controls. Interestingly, the ratio of the m6A writer METTL3 to m6A eraser FTO was also significantly high in naïve BM patient sample than controls. The expression of m6A readers IGF2BP1/3 that stabilize the methylated target mRNA, was also studied. IGF2BP1/3 m6A reader was significantly higher in naïve and relapsed patient samples. Increased expression of the writers and readers implied an increase in the m6A levels in B-ALL patients. The m6A% assay showed that the percentage of m6A was significantly higher in naïve and relapsed BM patient samples than both controls corroborating the RT-qPCR data. Discussion: METTL3 m6A methyl transferase has been identified a key factor in mediating the pathogenesis of AML. In our data, we have shown overexpression of METTL3 in B-ALL patient BM samples compared to controls. We have also seen an overexpression of m6A demethylase FTO in B-ALL patient samples. In order to identify the major factor among m6A writers and erasers that might play a role in pathogenesis of B-ALL, we calculated the ratio of m6A writer to m6A eraser. We have observed that ratio of METTL3 to ALKBH5 and METTL3 to FTO was significantly higher in B-ALL patient samples than both the controls. This signifies that overexpression of METTL3 subsequently leading to dysregulated methylation of its targets might influence the development and onset of relapse in B-ALL. It is well known that m6A bound target mRNAs are read by m6A readers like IGF2BPs that stabilize these m6A bound mRNAs leading to overexpression and thereby cancer progression. We have also studied expression of IGF2BP1/3 in B-ALL and seen significant overexpression of both IGF2BP1 and IGF2BP3 in B-ALL samples. These findings indicate a combined dysregulation of m6A writers, erasers and readers in B-ALL. This corroborates with the findings seen in AML, which also shows overexpression of METTL3, ALKBH5 and FTO. Our gene expression studies together point towards an increased percentage of m6A methylated RNA in B-ALL. We have evaluated the percentage of m6A in B-ALL patient samples to confirm our gene expression findings. We observed presence of significantly higher percentage of m6A in B-ALL patient samples (naïve and relapse) than both the controls. m6A% was significantly higher in naïve B-ALL patient samples compared to CD34+ HSCs also. Our findings reveal overall high m6A% in B-ALL, attributed to overexpression of m6A writer METTL3 and m6A readers IGF2BP1/3. This RNA methylation and stabilization might be dysregulated and concentrated in oncogenic genes leading to leukemogenesis. Our results provide a rationale for targeting of these m6A machinery genes dysregulation of which can be instrumental in pathogenesis of B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

2021 ◽  
Vol 12 ◽  
Author(s):  
Brandon J. Payliss ◽  
Ayushi Patel ◽  
Anneka C. Sheppard ◽  
Haley D. M. Wyatt
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Genome Instability ◽  
Strand Break ◽  
Biochemical Properties ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Recent Developments ◽  
And Function

All organisms depend on the ability of cells to accurately duplicate and segregate DNA into progeny. However, DNA is frequently damaged by factors in the environment and from within cells. One of the most dangerous lesions is a DNA double-strand break. Unrepaired breaks are a major driving force for genome instability. Cells contain sophisticated DNA repair networks to counteract the harmful effects of genotoxic agents, thus safeguarding genome integrity. Homologous recombination is a high-fidelity, template-dependent DNA repair pathway essential for the accurate repair of DNA nicks, gaps and double-strand breaks. Accurate homologous recombination depends on the ability of cells to remove branched DNA structures that form during repair, which is achieved through the opposing actions of helicases and structure-selective endonucleases. This review focuses on a structure-selective endonuclease called SLX1-SLX4 and the macromolecular endonuclease complexes that assemble on the SLX4 scaffold. First, we discuss recent developments that illuminate the structure and biochemical properties of this somewhat atypical structure-selective endonuclease. We then summarize the multifaceted roles that are fulfilled by human SLX1-SLX4 and its associated endonucleases in homologous recombination and genome stability. Finally, we discuss recent work on SLX4-binding proteins that may represent integral components of these macromolecular nuclease complexes, emphasizing the structure and function of a protein called SLX4IP.

scholarly journals RNA-binding proteins La and HuR cooperatively modulate translation repression of PDCD4 mRNA

2020 ◽  
pp. jbc.RA120.014894
Author(s):  
Ravi Kumar ◽  
Dipak Kumar Poria ◽  
Partho Sarothi Ray
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Suppressor Gene ◽  
Cooperative Action ◽  
Translation Repression

Post-transcriptional regulation of gene expression plays a critical role in controlling the inflammatory response. An uncontrolled inflammatory response results in chronic inflammation, often leading to tumorigenesis. Programmed cell death 4 (PDCD4) is a pro-inflammatory tumor-suppressor gene which helps to prevent the transition from chronic inflammation to cancer. PDCD4 mRNA translation is regulated by an interplay between the oncogenic microRNA miR-21 and the RNA-binding protein (RBP) HuR in response to LPS stimulation, but the role of other regulatory factors remain unknown. Here we report that the RBP Lupus antigen (La) interacts with the 3’UTR of PDCD4 mRNA and prevents miR-21-mediated translation repression. While LPS causes nuclear-cytoplasmic translocation of HuR, it enhances cellular La expression. Remarkably, La and HuR were found to bind cooperatively to the PDCD4 mRNA and mitigate miR-21-mediated translation repression. The cooperative action of La and HuR reduced cell proliferation and enhanced apoptosis, reversing the pro-oncogenic function of miR-21. Together, these observations demonstrate a cooperative interplay between two RBPs, triggered differentially by the same stimulus, which exerts a synergistic effect on PDCD4 expression and thereby helps maintain a balance between inflammation and tumorigenesis.

scholarly journals Lin28, a major translation reprogramming factor, gains access to YB-1-packaged mRNA through its cold-shock domain

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiia Samsonova ◽  
Krystel El Hage ◽  
Bénédicte Desforges ◽  
Vandana Joshi ◽  
Marie-Jeanne Clément ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cold Shock ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Binding Protein ◽  
Large Set ◽  
Core Component ◽  
The Core ◽  
Cold Shock Domain ◽  
Global Translation

AbstractThe RNA-binding protein Lin28 (Lin28a) is an important pluripotency factor that reprograms translation and promotes cancer progression. Although Lin28 blocks let-7 microRNA maturation, Lin28 also binds to a large set of cytoplasmic mRNAs directly. However, how Lin28 regulates the processing of many mRNAs to reprogram global translation remains unknown. We show here, using a structural and cellular approach, a mixing of Lin28 with YB-1 (YBX1) in the presence of mRNA owing to their cold-shock domain, a conserved β-barrel structure that binds to ssRNA cooperatively. In contrast, the other RNA binding-proteins without cold-shock domains tested, HuR, G3BP-1, FUS and LARP-6, did not mix with YB-1. Given that YB-1 is the core component of dormant mRNPs, a model in which Lin28 gains access to mRNPs through its co-association with YB-1 to mRNA may provide a means for Lin28 to reprogram translation. We anticipate that the translational plasticity provided by mRNPs may contribute to Lin28 functions in development and adaptation of cancer cells to an adverse environment.

scholarly journals The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Xinyun Chen ◽  
Jianwen Yin ◽  
Dayan Cao ◽  
Deyong Xiao ◽  
Zhongjun Zhou ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Property ◽  
Cardiovascular Development ◽  
Potential Link ◽  
Alternatively Spliced ◽  
Unique Cell ◽  
Carboxy Terminal ◽  
And Function

RNA binding proteins (RBPs) have a broad biological and physiological function and are critical in regulating pre-mRNA posttranscriptional processing, intracellular migration, and mRNA stability. QKI, also known as Quaking, is a member of the signal transduction and activation of RNA (STAR) family, which also belongs to the heterogeneous nuclear ribonucleoprotein K- (hnRNP K-) homology domain protein family. There are three major alternatively spliced isoforms, QKI-5, QKI-6, and QKI-7, differing in carboxy-terminal domains. They share a common RNA binding property, but each isoform can regulate pre-mRNA splicing, transportation or stability differently in a unique cell type-specific manner. Previously, QKI has been known for its important role in contributing to neurological disorders. A series of recent work has further demonstrated that QKI has important roles in much broader biological systems, such as cardiovascular development, monocyte to macrophage differentiation, bone metabolism, and cancer progression. In this mini-review, we will focus on discussing the emerging roles of QKI in regulating cardiac and vascular development and function and its potential link to cardiovascular pathophysiology.

scholarly journals PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

2018 ◽  
Vol 115 (8) ◽  
pp. E1759-E1768 ◽  
Author(s):  
Jung-Kuei Chen ◽  
Wen-Ling Lin ◽  
Zhang Chen ◽  
Hung-wen Liu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Strand Break ◽  
Double Strand Break ◽  
Dsb Repair ◽  
Active Involvement ◽  
Parp 1

Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced γH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.

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