Genetic Characterization of Three Distinct Mechanisms Supporting RNA-Driven DNA Repair and Modification Reveals Major Role of DNA Polymerase ζ

Meers, Chance; Keskin, Havva; Bányai, Gábor; Mazina, Olga M.; Yang, Taehwan; Gombolay, Alli L.; Mukherjee, Kakali; Kaparos, Efiyenia I.; Newnam, Gary P.; Mazin, Alexander V.; Storici, Francesca

doi:10.1016/j.molcel.2020.08.011

Cited by 33 publications

(34 citation statements)

References 81 publications

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“…Although the mechanistic details remain to be fleshed out, it has been proposed that the RNAbinding activity of RPA induces a conformational change in RAD52 that favors strand exchange between DSB ends and homologous RNA templates (Keskin et al, 2014;Mazina et al, 2017). In budding yeast, translesion DNA polymerase ζ is able to reverse transcribe RNA and use it as a repair template at DSB sites (Meers et al, 2020). It will be important to test whether human Pol ζ or other human DNA polymerases similarly promote reverse transcription to fill in gaps during RNA-templated DNA repair.…”

Section: Rna-binding Protein-rna Interactions Are Central To Double-strand Break Signaling and Repairmentioning

confidence: 99%

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

Klaric

Wüst

Panier

2021

Front. Mol. Biosci.

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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.

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Section: Rna-binding Protein-rna Interactions Are Central To Double-strand Break Signaling and Repairmentioning

confidence: 99%

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

Klaric

Wüst

Panier

2021

Front. Mol. Biosci.

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“…Given that ribonucleotides are the most frequently occurring nucleotide lesion in genomic DNA that arrest replicative Pols and cause DNA breaks ( 19 , 20 ), we also envisaged that Polθ would tolerate template ribonucleotides during its DNA repair activities and thus promote RNA-templated DNA repair synthesis (RNA-DNA repair). Although RNA-DNA repair mechanisms have been demonstrated in genetically engineered yeast cells ( 21 , 22 ), they remain obscure in mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Polθ reverse transcribes RNA and promotes RNA-templated DNA repair

et al. 2021

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Genome-embedded ribonucleotides arrest replicative DNA polymerases (Pols) and cause DNA breaks. Whether mammalian DNA repair Pols efficiently use template ribonucleotides and promote RNA-templated DNA repair synthesis remains unknown. We find that human Polθ reverse transcribes RNA, similar to retroviral reverse transcriptases (RTs). Polθ exhibits a significantly higher velocity and fidelity of deoxyribonucleotide incorporation on RNA versus DNA. The 3.2-Å crystal structure of Polθ on a DNA/RNA primer-template with bound deoxyribonucleotide reveals that the enzyme undergoes a major structural transformation within the thumb subdomain to accommodate A-form DNA/RNA and forms multiple hydrogen bonds with template ribose 2′-hydroxyl groups like retroviral RTs. Last, we find that Polθ promotes RNA-templated DNA repair in mammalian cells. These findings suggest that Polθ was selected to accommodate template ribonucleotides during DNA repair.

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“…HDR may be directed by an RNA template, which has been discovered and mechanistically explored in yeast [ 123 ]. A recent study showed that RNA-templated recombination in postmitotic neurons occurred with the involvement of RAD52 and that the affinity of RAD52 to RNA might exceed that to DNA [ 124 ].…”

Section: Discussionmentioning

confidence: 99%

Single-Strand Annealing in Cancer

Błasiak

2021

IJMS

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DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.

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Genetic Characterization of Three Distinct Mechanisms Supporting RNA-Driven DNA Repair and Modification Reveals Major Role of DNA Polymerase ζ

Cited by 33 publications

References 81 publications

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

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

Polθ reverse transcribes RNA and promotes RNA-templated DNA repair

Single-Strand Annealing in Cancer

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