Mechanism of tandem duplication formation in BRCA1-mutant cells

Willis, Nicholas A.; Frock, Richard L.; Menghi, Francesca; Duffey, Erin E.; Panday, Arvind; Camacho, Virginia; Hasty, Paul; Liu, Edison T.; Alt, Frederick W.; Scully, Ralph

doi:10.1038/nature24477

Cited by 129 publications

(182 citation statements)

References 52 publications

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“…Further validating this model, we have recently defined the mechanism of TD formation in BRCA1 mutant cells in a murine cell culture model (Willis et al, 2017). We find that TDs form at sites of replication fork stalling in BRCA1 mutant cells by a mechanism that entails re-replication of kilobases-long tracts of chromosomal DNA adjacent to the site of fork stalling.…”

Section: Brca2mentioning

confidence: 84%

The Tandem Duplicator Phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations

Menghi

Barthel

Yadav

et al. 2017

Preprint

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SUMMARYThe tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 Kb, 231 Kb, and 1.7 Mb. TDPs with prominent ~11 Kb TDs feature the conjoint loss of TP53 and BRCA1. TDPs with ~231 Kb and ~1.7 Mb TDs associate with CCNE1 pathway activation or CDK12 disruptions, in conjunction with TP53 mutations. We prove the driver role of TP53 and BRCA1 abrogation for TDP induction by generating short-span TDP mammary tumors in genetically modified mouse models harboring deleterious mutations in only these two genes. Lastly, heterogeneous combinations of mutations mediated by TDs are selected for and contribute to the oncogenic burden of TDP tumors.

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Section: Brca2mentioning

confidence: 84%

The Tandem Duplicator Phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations

Menghi

Barthel

Yadav

et al. 2017

Preprint

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“…Our genome graphs provide a starting point for rigorous classification of complex SV patterns, but only lend partial insight into mechanism. For example, it is unclear whether pyrgo represent another facet of the "tandem duplicator phenotype" (Menghi et al, 2016;Viswanathan et al, 2018;Willis et al, 2017) or arise from a completely independent mechanism. Additional mechanistic insight into the genesis of complex SV will likely require the consideration of junction phase, as shown with our 10X Chromium WGS analysis of rigma.…”

Section: Discussionmentioning

confidence: 99%

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Hadi

Yao

et al. 2019

Preprint

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Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise "chasms" of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis. Cancer genomics | Structural variation | DNA rearrangements | Mutational Processes | Genome graphs | Copy number alterationsCorrespondence: mski@mskilab.org K. Hadi, X.Yao, J. Behr et al. | bioRχiv | November 12, 2019 | 1-8

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“…The insertion of a cytosine residue into the pocket locks the binding of Tus to Ter, which explains the orientation‐dependent pausing of the replicative helicase and the replication fork . Tus–Ter induced in mammalian cells blocks replication forks and induces homologous recombination via a BRCA1 pathway . However, the fork block occurs bidirectionally, probably because the simple binding of Tus to Ter is sufficient to pause the replicative helicase and eventually the replication fork .…”

Section: Orientation‐dependent Fork Block At the Sites Of Programed Fmentioning

confidence: 99%

Replication fork pausing at protein barriers on chromosomes

Hizume

Araki

2019

FEBS Letters

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When a cell divides prior to completion of DNA replication, serious DNA damage may occur. Thus, in addition to accuracy, the processivity of the replication forks is important. DNA synthesis at replication forks should be completed in time, and forks overcome aberrant structures on the template DNA, including damaged sites, using trans‐lesion synthesis, occasionally introducing mutations. By contrast, the protein barrier built on the DNA is known to block the progression of replication forks at specific chromosomal loci. Such protein barriers avert any collision of replication and transcription machineries, or control the recombination of specific loci. The components and the mechanisms of action of protein barriers have been revealed mainly using genetic and biochemical techniques. In addition to proteins involved in replication fork pausing, the interaction of the replicative helicase and DNA polymerase is also essential for replication fork pausing. Here, we provide an overview of replication fork pausing at protein barriers.

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Mechanism of tandem duplication formation in BRCA1-mutant cells

Cited by 129 publications

References 52 publications

The Tandem Duplicator Phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations

The Tandem Duplicator Phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Replication fork pausing at protein barriers on chromosomes

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