The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki, Keiko; Murnane, John P.

doi:10.1266/ggs.17-00014

Cited by 17 publications

(13 citation statements)

References 207 publications

(290 reference statements)

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“…Interestingly, 16 of the 22 locations involved in the translocations were in sub-telomeric regions, which occurred in 8 pairs where both locations were near telomeres. This is consistent with previous studies reporting that rearrangements involving telomeres and subtelomeres may be a common form of translocation in humans (Bailey and Murnane 2006, Liddiard et al 2016, Muraki and Murnane 2018). We examined the translocation between chromosomes 15 and 20, which contains three of the genes in Table 4, by looking more closely at the alignment between GRCh38 and Ash1.…”

Section: Annotationsupporting

confidence: 93%

Assembly and Annotation of an Ashkenazi Human Reference Genome

Shumate

Zimin

Sherman

et al. 2020

Preprint

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Here we describe the assembly and annotation of the genome of an Ashkenazi individual and the creation of a new, population-specific human reference genome. This genome is more contiguous and more complete than GRCh38, the latest version of the human reference genome, and is annotated with highly similar gene content. The Ashkenazi reference genome, Ash1, contains 2,973,118,650 nucleotides as compared to 2,937,639,212 in GRCh38. Annotation identified 20,157 protein-coding genes, of which 19,563 are >99% identical to their counterparts on GRCh38. Most of the remaining genes have small differences. 40 of the protein-coding genes in GRCh38 are missing from Ash1; however, all of these genes are members of multi-gene families for which Ash1 contains other copies. 11 genes appear on different chromosomes from their homologs in GRCh38. Alignment of DNA sequences from an unrelated Ashkenazi individual to Ash1 identified ~1 million fewer homozygous SNPs than alignment of those same sequences to the more-distant GRCh38 genome, illustrating one of the benefits of population-specific reference genomes.

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Section: Annotationsupporting

confidence: 93%

Assembly and Annotation of an Ashkenazi Human Reference Genome

Shumate

Zimin

Sherman

et al. 2020

Preprint

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“…In cells with dysfunctional telomeres, chromosome ends are no longer protected efficiently by the shelterin components. These unprotected telomeres resemble chromosome breaks and activate the DNA-damage response [155][156][157] . Furthermore, they are prone to degradation by exonucleases and lose their capping function to protect from end-to-end fusions or loss of genetic material.…”

Section: [H1]opportunities In Diagnosis and Therapymentioning

confidence: 99%

Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis

et al. 2018

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Telomerase activity imparts eukaryotic cells with unlimited proliferation capacity, one of the cancer hallmarks. Over 90% of human urothelial carcinoma of the bladder (UCB) tumours are positive for telomerase activity. Telomerase activation can occur through several mechanisms. Mutations in the core promoter region of the human telomerase reverse transcriptase gene (TERT) cause telomerase reactivation in 60-80% of UCBs, whereas the prevalence of these mutations is lower in urothelial cancers of other origins. TERT promoter mutations are the most frequent genetic alteration across all stages of UCB, indicating a strong selection pressure during neoplastic transformation. TERT promoter mutations could arise during regeneration of normal urothelium and, owing to consequential telomerase reactivation, might be the basis of UCB initiation, which represents a new model of urothelial cancer origination. In the future, TERT promoter mutations and telomerase activity might have diagnostic and therapeutic applications in UCB.

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“…Another process is BIR repair of collapsed replication forks, which expands tandem rDNA repeat arrays (Kobayashi 2014). In the companion paper (Rice 2020), I explore the hypothesis that low sequence identity among nearby monomers is favored by molecular drive (Dover 1082) because it reduces the rate of deletions during repair of double strand breaks via SSA repair pathway -a repair mechanism that is expected to occur at elevated rates within the centromeres of telocentric chromosomes (Muraki and Murnane 2017).…”

Section: Discussionmentioning

confidence: 99%

Centromeric repeats of the Western European house mouse I: high sequence diversity among monomers at local and global spatial scales

Rice

2020

Preprint

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Previous work found that the centromeric repeats of the Western European house mouse (Mus musculus domesticus) are composed predominantly of a 120 bp monomer that is shared by the X and autosomes. Polymorphism in length and sequence was also reported. Here I quantified the length and sequence polymorphism of the centromeric repeats found on the X and autosomes. The levels of local and global sequence variation were also compared. I found three length variants: a 64mer, 112mer and 120mer with relative frequencies of 2.4%, 8.6%, and 89%, respectively. There was substantial sequence variation within all three length variants with a rank-order of: 64mer < 120mer < 112mer. The 64mer was never found alone on long Sanger traces, and was arranged predominantly as a 176 bp higher-order repeat composed of a 64/112mer dimer. Reanalysis of archived ChIP-seq reads found that all three length variants were enriched with the foundational centromere protein CENP-A, but the enrichment was far higher for the 120mer. This pattern indicates that only the 120mer contributes substantially to the functional centromeres, i.e., to the kinetochore-binding, centric cores of the centromeric repeat arrays. Despite only moderate sequence divergence among random pairs of 120mers (averaging 5.9%), other measures of sequence diversity were exceptionally high: i) variant richness (numerical diversity) –on average, one new sequence variant was observed every 4th additional monomer randomly sampled (in N = 7.2 × 103 monomers), and ii) variant evenness –all of the nearly 2 × 103 observed sequence variants were at low frequency, with the most common variant having a frequency of only 5.7%. I next used long Sanger trace data from the Mouse Genome Project to assess the pattern of monomer diversity among neighboring 120mers. Unexpectedly, side-by-side monomers were rarely identical in sequence, and sequence divergence between these neighbors was nearly as high as that between random pairs taken from the genome-wide pool of all 120mers. I also used long Sanger traces to determine sequence variation among neighborhoods of 5 contiguous 120 bp monomers. Sequence diversity within these small regions typically spanned most of the entire range of that found genome-wide. Despite high sequence variation within these neighborhoods, the density of monomers with functional binding motifs for CENP-B (i.e., b-boxes with sequence NTTCGNNNNANNCGGGN) was strongly conserved at about 50%. The overarching pattern of monomer structure at the centromeric repeats of this subspecies is: i) high homogeneity in the density CENP-B binding sites, and ii) high heterogeneity in monomer sequence at both local and global levels.

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The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Cited by 17 publications

References 207 publications

Assembly and Annotation of an Ashkenazi Human Reference Genome

Assembly and Annotation of an Ashkenazi Human Reference Genome

Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis

Centromeric repeats of the Western European house mouse I: high sequence diversity among monomers at local and global spatial scales

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