Mutagenic consequences of a single G-quadruplex demonstrate mitotic inheritance of DNA replication fork barriers

Lemmens, Bennie B. L. G.; Schendel, Robin van; Tijsterman, Marcel

doi:10.1038/ncomms9909

Cited by 113 publications

(110 citation statements)

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“…We speculate that particularly DSBs that occur in S‐phase but cannot use a non‐damaged sister chromatid as a repair donor, may heavily rely on TMEJ. These could be DSBs that occur in DNA segments that are not yet replicated, or DSBs induced at sites opposite a damaged sister chromatid (Lemmens et al , ). Also transposon mobilization, when co‐occurring at both sister chromatids, may be a physiological source of DSBs that completely rely on TMEJ for their repair (van Schendel et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…Pol θ and its related mutational signature are evolutionary conserved and were first described in Drosophila melanogaster, where Pol θ can repair DSBs induced by endonucleases or P element transposition (Chan et al , ). In the nematode Caenorhabditis elegans , Pol θ is required for the repair of replication stress‐associated DSBs that form at persistent replication‐blocking lesions and G‐quadruplex structures in DNA (Koole et al , ; Roerink et al , ; Lemmens et al , ; van Schendel et al , , ). Several lines of evidence have also implicated Pol θ in Alt‐EJ in mouse cells: TMEJ provides resistance to DNA strand breaking agents in bone marrow stromal cells (Yousefzadeh et al , ), TMEJ‐like footprints were observed at junctions of fused dysfunctional telomeres in embryonic fibroblasts (Mateos‐Gomez et al , ), and TMEJ was found to regulate the repair of exogenous DNA substrates (Yousefzadeh et al , ; Wyatt et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Mutational signatures of non‐homologous and polymerase theta‐mediated end‐joining in embryonic stem cells

et al. 2017

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Cells employ potentially mutagenic DNA repair mechanisms to avoid the detrimental effects of chromosome breaks on cell survival. While classical non‐homologous end‐joining (cNHEJ) is largely error‐free, alternative end‐joining pathways have been described that are intrinsically mutagenic. Which end‐joining mechanisms operate in germ and embryonic cells and thus contribute to heritable mutations found in congenital diseases is, however, still largely elusive. Here, we determined the genetic requirements for the repair of CRISPR/Cas9‐induced chromosomal breaks of different configurations, and establish the mutational consequences. We find that cNHEJ and polymerase theta‐mediated end‐joining (TMEJ) act both parallel and redundant in mouse embryonic stem cells and account for virtually all end‐joining activity. Surprisingly, mutagenic repair by polymerase theta (Pol θ, encoded by the Polq gene) is most prevalent for blunt double‐strand breaks (DSBs), while cNHEJ dictates mutagenic repair of DSBs with protruding ends, in which the cNHEJ polymerases lambda and mu play minor roles. We conclude that cNHEJ‐dependent repair of DSBs with protruding ends can explain de novo formation of tandem duplications in mammalian genomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutational signatures of non‐homologous and polymerase theta‐mediated end‐joining in embryonic stem cells

et al. 2017

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“…A possible insight is provided by analysis of nematodes, where a single quadruplex has been shown to persist through multiple generations, arresting replication to create a 3′ end bordering a gap that is converted to a DSB during DNA replication (27). …”

Section: Discussionmentioning

confidence: 99%

Initiation of homologous recombination at DNA nicks

Maizels

Davis

2018

Nucleic Acids Research

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Discontinuities in only a single strand of the DNA duplex occur frequently, as a result of DNA damage or as intermediates in essential nuclear processes and DNA repair. Nicks are the simplest of these lesions: they carry clean ends bearing 3′-hydroxyl groups that can undergo ligation or prime new DNA synthesis. In contrast, single-strand breaks also interrupt only one DNA strand, but they carry damaged ends that require clean-up before subsequent steps in repair. Despite their apparent simplicity, nicks can have significant consequences for genome stability. The availability of enzymes that can introduce a nick almost anywhere in a large genome now makes it possible to systematically analyze repair of nicks. Recent experiments demonstrate that nicks can initiate recombination via pathways distinct from those active at double-strand breaks (DSBs). Recombination at targeted DNA nicks can be very efficient, and because nicks are intrinsically less mutagenic than DSBs, nick-initiated gene correction is useful for genome engineering and gene therapy. This review revisits some physiological examples of recombination at nicks, and outlines experiments that have demonstrated that nicks initiate homology-directed repair by distinctive pathways, emphasizing research that has contributed to our current mechanistic understanding of recombination at nicks in mammalian cells.

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“…Recent studies have suggested that epigenetic factors, DNA structures, and sequence motif influence the mutation rate (8,9,23,24). However, little is known about factors that influence the mutability of microsatellites.…”

Section: Mutability Of Microsatellitementioning

confidence: 99%

“…We considered replication timing, nuclear lamina binding region, G-quadruplexes, and predicted DNA shapes. Nuclear lamina binding regions are known to be associated with genomic fragile sites (23), while G-quadruplexes can cause replication errors (24). The impact of DNA shapes was not well known, but one DNA shape parameter (ORChID2) had been reported to be associated with mutation rate of somatic indels (9).…”

Section: Mutability Of Microsatellitementioning

confidence: 99%

Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types

Fujimoto

Fujita

Hasegawa

et al. 2018

Preprint

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20Microsatellites are repeats of 1-6bp units and ~10 million microsatellites have been 21 identified across the human genome. Microsatellites are vulnerable to DNA mismatch 22 germline variation of the microsatellites suggested that the amount of germline variations 34 and somatic mutation rates were correlated. Lastly, analysis of mutations in mismatch 35 repair genes showed that somatic SNVs and short indels had larger functional impact than 36 germline mutations and structural variations. Our analysis provides a comprehensive 37 picture of mutations in the microsatellite regions, and reveals possible causes of mutations, 38as well as provides a useful marker set for MSI detection. 39 40Introduction 41Recent large-scale whole genome sequencing studies have revealed the complexity of the 42 mutational landscape of the cancer genome (1-4). In cancer genomes, various types of 43 mutations, such as SNVs (single nucleotide variants), short indels (insertions and 44 deletions), genomic rearrangements, copy number alterations, insertion of 45 retrotransposons, and virus genome integrations, have been identified, and their 46 oncogenic roles have been characterized (1-5). Additionally, genome sequencing studies 47 have revealed the molecular basis of somatic mutations (6-9). However, somatic 48 mutations in microsatellites or repeat sequences have not been well-characterized in a 49 large whole genome sequencing cohort due to difficulties in accurately detecting 50 mutations using presently available short-read sequencing technologies. 51A microsatellite is defined as a tract of repetitive DNA motif composed of short 52 repeating units (10). The mutation rate of microsatellites has been known to be higher 53 than other genomic regions due to DNA polymerase slippage during DNA replication and 54 repair (10). Due to their fragility, microsatellites are used as markers of genomic 55 instability in cancer (11). In cancer genetics studies, microsatellite instability (MSI) has 56 been used for molecular diagnosis of Lynch syndrome and cancers with mismatch repair 57 deficiency (11). Furthermore, MSI-positive tumors are generally burdened with higher 58 numbers of somatic mutations and present many mutation-associated neo-antigens, which 59 might be recognized by the immune system. Presently, MSI can also be used as a marker 60 to predict the effect of immune therapy (12). The MSI phenotype is most common in 61 colorectal cancers, stomach cancers and uterine endometrial cancers (10-15%), although 62 it has also been observed across many tumor types at a few % (11). The MSI phenotype 63 is defined by the presence of somatic indels of the 2-5 microsatellite makers, whereby 64 BAT25/26 mononucleotide microsatellites are widely used to establish MSI status (11). 65Irrespective of the clinical importance of microsatellite, large-scale analysis of 66 somatic changes in microsatellites across various type of cancers is limited for whole 67 genome sequencing (WGS) data (13, 14). In the current study, we analyzed indels in 68 microsat...

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Mutagenic consequences of a single G-quadruplex demonstrate mitotic inheritance of DNA replication fork barriers

Cited by 113 publications

References 29 publications

Mutational signatures of non‐homologous and polymerase theta‐mediated end‐joining in embryonic stem cells

Mutational signatures of non‐homologous and polymerase theta‐mediated end‐joining in embryonic stem cells

Initiation of homologous recombination at DNA nicks

Comprehensive Analysis of Indels in Whole-genome Microsatellite Regions and Microsatellite Instability across 21 Cancer Types

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