AI Article Synopsis

  • - G-quadruplex (G4) structures in DNA can impact crucial processes like replication and transcription in mammalian genomes; this study specifically looked at G4 structures linked to the PKD1 gene.
  • - The researchers engineered cells to study how G4 stabilization leads to DNA deletions and double-strand breaks, highlighting the role of a specific nuclease (Mus81) and showing that this instability can extend beyond the immediate G4 location.
  • - They discovered that both G4 and triplex (H3) structures cause genomic instability, but they display different behaviors during cell growth, with G4 structures losing stability earlier, which informs our understanding of how DNA repair processes contribute to genetic mutations.

Article Abstract

G-quadruplex (G4)-prone structures are abundant in mammalian genomes, where they have been shown to influence DNA replication, transcription, and genome stability. In this article, we constructed cells with a single ectopic homopurine/homopyrimidine repeat tract derived from the polycystic kidney disease type 1 (PKD1) locus, which is capable of forming triplex (H3) and G4 DNA structures. We show that ligand stabilization of these G4 structures results in deletions of the G4 consensus sequence, as well as kilobase deletions spanning the G4 and ectopic sites. Furthermore, we show that DNA double-strand breaks at the ectopic site are dependent on the nuclease Mus81. Hypermutagenesis during sister chromatid repair extends several kilobases from the G4 site and breaks at the G4 site resulting in microhomology-mediated translocations. To determine whether H3 or G4 structures are responsible for homopurine/homopyrimidine tract instability, we derived constructs and cell lines from the PKD1 repeat, which can only form H3 or G4 structures. Under normal growth conditions, we found that G4 cell lines lost the G4 consensus sequence early during clonal outgrowth, whereas H3 cells showed DNA instability early during outgrowth but only lost reporter gene expression after prolonged growth. Thus, both the H3 and G4 non-B conformation DNAs exhibit genomic instability, but they respond differently to endogenous replication stress. Our results show that the outcomes of replication-dependent double-strand breaks at non-B-DNAs model the instability observed in microhomology-mediated break-induced replication (BIR). Marked variability in the frequency of mutagenesis during BIR suggests possible dynamic heterogeneity in the BIR replisome.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142560PMC
http://dx.doi.org/10.1016/j.jbc.2022.101947DOI Listing

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