DNA polymerase beta and other gap-filling enzymes in mammalian base excision repair

Beard, William A.; Wilson, Samuel H.

doi:10.1016/bs.enz.2019.08.002

Cited by 28 publications

(18 citation statements)

References 78 publications

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“…It has also been suggested that the MutS␤-Pol␤ complex may promote CAG-repeat expansion during base excision repair (BER) [202,203], although the interplay between the MMR and BER pathways in CAGrepeat expansion remains to be fully dissected [26]. Also, given the limited processivity of Pol␤ (1-6 nucleotides) [204], it is unclear as to how it might carry out error-prone synthesis of disease-relevant CAG repeat tracts. Error-prone DNA synthesis has also been invoked to explain non-canonical MMRmediated mutagenesis [23].…”

Section: Mechanisms Of Mmr-mediated Cag Repeat Expansionmentioning

confidence: 99%

DNA Mismatch Repair and its Role in Huntington’s Disease

Iyer

Pluciennik

2021

JHD

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DNA mismatch repair (MMR) is a highly conserved genome stabilizing pathway that corrects DNA replication errors, limits chromosomal rearrangements, and mediates the cellular response to many types of DNA damage. Counterintuitively, MMR is also involved in the generation of mutations, as evidenced by its role in causing somatic triplet repeat expansion in Huntington’s disease (HD) and other neurodegenerative disorders. In this review, we discuss the current state of mechanistic knowledge of MMR and review the roles of key enzymes in this pathway. We also present the evidence for mutagenic function of MMR in CAG repeat expansion and consider mechanistic hypotheses that have been proposed. Understanding the role of MMR in CAG expansion may shed light on potential avenues for therapeutic intervention in HD.

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Section: Mechanisms Of Mmr-mediated Cag Repeat Expansionmentioning

confidence: 99%

DNA Mismatch Repair and its Role in Huntington’s Disease

Iyer

Pluciennik

2021

JHD

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“…Overall, BER, and the parallel sub-pathway single-stand break repair (SSBR), are both critical DNA repair pathways that are found in all species and are deemed essential for the resolution of base lesions and DNA single-strand breaks in both the nuclear and mitochondrial genomes. Extensive reviews on BER and SSBR are, of course, available [201,[294][295][296][297][298][299][300][301][302]. As described in an elegant summary by Wilson and Kunkel, BER enzymes pass the resulting enzymatic products of each reaction of the repair mechanism to the next enzyme in the pathway [303], thereby avoiding the accumulation of genome destabilizing BER intermediates [304].…”

Section: Advances In Ber Biology By Exploiting Gene Editing Technologiesmentioning

confidence: 99%

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Thompson

Sobol

Prakash

2021

Biology

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The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.

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“…The key 'scaffold' protein in BER is X-ray cross complementing factor 1 (XRCC1), upon which additional repair proteins are assembled [6]. An important contributor to short patch repair is DNA polymerase b (polb), which plays dual roles in tidying up damaged DNA ends and filling in missing nucleotides, using the intact DNA strand as a template [7]. Other players include apurinic/apyrimidinic endonuclease-1 (APE1), which assists in resecting damaged termini, and DNA ligase III (Lig3), which executes the final step of sealing the resynthesised strand.…”

Section: Base Excision Repairmentioning

confidence: 99%