Emerging Roles of DNA Glycosylases and the Base Excision Repair Pathway

Mullins, E.A.; Rodriguez, Alyssa A.; Bradley, Noah P.; Eichman, Brandt F.

doi:10.1016/j.tibs.2019.04.006

Cited by 83 publications

(68 citation statements)

References 97 publications

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“…Naturally, APOBEC enzymes catalyze the deamination of cytidine (C) to uridine (U) in single-strand RNA or DNA (ssDNA) regions [52][53][54]. Since uracil in DNA is usually a signal for base excision repair (BER), an endogenous DNA repair pathway to remove base lesions, such as uracil, in genome [55,56], a uracil DNA glycosylase inhibitor (UGI) [57] repair erroneous short insertion, deletion, and mis-incorporation of bases. In D10A-mediated base editing where a C-to-U (or A-to-I) change happens, MMR resolves the U/G (or I/T) mismatch to a U/A (or I/C) pair, which can be then converted to a T/A (or G/C) base pair after DNA replication or repair.…”

Section: Adopting Naturally Existing Cytidine Deaminase Effector For mentioning

confidence: 99%

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

Yang

Chen

2020

Trends in Biochemical Sciences

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Highlights CRISPR/Cas with different modules for independent target binding and cleavage has evolved to achieve convenient and precise genome editing. The endonuclease effector in conventional CRISPR/Cas genome editing systems can be replaced by nucleobase deaminases and the resulting base editors (BEs) enable single base changes. By fusing CRISPR/Cas with reverse transcriptases, prime editors (PEs) represent a new way to accomplish genetic changes, including all types of base substitutions, small indels, and their combinations. Both BEs and PEs are of potential in correcting disease-associated mutations. Genome-wide and/or transcriptomewide off-target mutations are catalyzed by the nucleobase deaminase effector in BEs, which are independent of the fused gRNA/Cas moiety.

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Section: Adopting Naturally Existing Cytidine Deaminase Effector For mentioning

confidence: 99%

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

Yang

Chen

2020

Trends in Biochemical Sciences

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“…Mammalian cells suffer~50 DSBs per cell cycle [3,4], largely as a result of replication stress when forks encounter DNA lesions, collide with transcription machinery, or encounter difficult to replicate sequences including fragile sites, sequences that can form G-quadraplexes, and sequences that stably associate with proteins [5][6][7][8]. DSBs are also generated when closely opposed single-strand lesions are processed by base excision repair (BER) or nucleotide excision repair (NER), as these processes create intermediates with SSBs or single-strand gaps [9][10][11][12]. Both isolated and clustered DSBs are induced by ionizing radiation [13].…”

Section: Introductionmentioning

confidence: 99%

“…Decades of reductionist research has revealed hundreds of distinct types of DNA lesions and defined how they are induced and repaired, and their mutagenic potential, genome destabilizing properties, and cytotoxic properties [9][10][11]14]. The many types of "simple" base lesions are repaired by base-excision repair, comprising families of glycosylases, AP endonucleases, and accessory factors, including end-processing enzymes, DNA polymerases, and DNA ligase [10,11]. Bulky adducts are helix-distorting lesions such as UV-induced pyrimidine dimers, and are repaired by nucleotide excision repair (NER), comprising both global NER and transcription-coupled NER [9,15].…”

Section: Introductionmentioning

confidence: 99%

Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy

Nickoloff

Sharma

Taylor

2020

Genes

144

108

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Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically “dirty” DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation.

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“…AlkZ expression is induced during production of AZB, and cells that express alkZ are resistant to the cytotoxic effects of AZB, even across different bacterial species ( 14 ). Thus, the AlkZ glycosylase provides self-resistance to the toxicity of these compounds in the producing organism ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

OUP accepted manuscript

Bradley

Washburn

Christov

et al. 2020

Nucleic Acids Research

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Interstrand DNA crosslinks (ICLs) are a toxic form of DNA damage that block DNA replication and transcription by tethering the opposing strands of DNA. ICL repair requires unhooking of the tethered strands by either nuclease incision of the DNA backbone or glycosylase cleavage of the crosslinked nucleotide. In bacteria, glycosylase-mediated ICL unhooking was described in Streptomyces as a means of self-resistance to the genotoxic natural product azinomycin B. The mechanistic details and general utility of glycosylase-mediated ICL repair in other bacteria are unknown. Here, we identify the uncharacterized Escherichia coli protein YcaQ as an ICL repair glycosylase that protects cells against the toxicity of crosslinking agents. YcaQ unhooks both sides of symmetric and asymmetric ICLs in vitro , and loss or overexpression of ycaQ sensitizes E. coli to the nitrogen mustard mechlorethamine. Comparison of YcaQ and UvrA-mediated ICL resistance mechanisms establishes base excision as an alternate ICL repair pathway in bacteria.

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Emerging Roles of DNA Glycosylases and the Base Excision Repair Pathway

Cited by 83 publications

References 97 publications

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy

OUP accepted manuscript

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