Characterization at nucleotide resolution of the homogeneously staining region sites of insertion in two cancer cell lines

Gibaud, Anne; Vogt, Nicolas; Brison, Olivier; Debatisse, Michèlle; Malfoy, Bernard

doi:10.1093/nar/gkt566

Cited by 14 publications

(19 citation statements)

References 37 publications

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“…Therefore, HR may not participate in the formation of intrachromosomal amplicons. This finding is consistent with those reported by Gibaud A's, in which whole‐genome analysis detected no breakpoint junction sequences that would support reconnection of broken amplicon ends by HR . Although the classical model of HSR formation based on the fusion of two sister chromatids, B‐F‐B, most probably correlates with HR, our results do not demonstrate a relationship between these two pathways.…”

Section: Discussionmentioning

confidence: 90%

Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate‐resistant colon cancer cells

Cai

Zhang

Hou

et al. 2018

Intl Journal of Cancer

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Gene amplification, which involves the two major topographical structures double minutes (DMs) and homegeneously stained region (HSR), is a common mechanism of treatment resistance in cancer and is initiated by DNA double-strand breaks. NHEJ, one of DSB repair pathways, is involved in gene amplification as we demonstrated previously. However, the involvement of homologous recombination, another DSB repair pathway, in gene amplification remains to be explored. To better understand the association between HR and gene amplification, we detected HR activity in DM- and HSR-containing MTX-resistant HT-29 colon cancer cells. In DM-containing MTX-resistant cells, we found increased homologous recombination activity compared with that in MTX-sensitive cells. Therefore, we suppressed HR activity by silencing BRCA1, the key player in the HR pathway. The attenuation of HR activity decreased the numbers of DMs and DM-form amplified gene copies and increased the exclusion of micronuclei and nuclear buds that contained DM-form amplification; these changes were accompanied by cell cycle acceleration and increased MTX sensitivity. In contrast, BRCA1 silencing did not influence the number of amplified genes and MTX sensitivity in HSR-containing MTX-resistant cells. In conclusion, our results suggest that the HR pathway plays different roles in extrachromosomal and intrachromosomal gene amplification and may be a new target to improve chemotherapeutic outcome by decreasing extrachromosomal amplification in cancer.

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Section: Discussionmentioning

confidence: 90%

Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate‐resistant colon cancer cells

Cai

Zhang

Hou

et al. 2018

Intl Journal of Cancer

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“…Interestingly, two fragile sites mapping within 8q24 [FRA8C (8q24.1) and FRA8D (8q24.3)] were shown to be prone to breakage when cell lines harboring MYC- containing hsr were exposed to aphidicolin (31). …”

Section: Discussionmentioning

confidence: 99%

Genomic organization and evolution of double minutes/homogeneously staining regions withMYCamplification in human cancer

et al. 2014

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The mechanism for generating double minutes chromosomes (dmin) and homogeneously staining regions (hsr) in cancer is still poorly understood. Through an integrated approach combining next-generation sequencing, single nucleotide polymorphism array, fluorescent in situ hybridization and polymerase chain reaction-based techniques, we inferred the fine structure of MYC-containing dmin/hsr amplicons harboring sequences from several different chromosomes in seven tumor cell lines, and characterized an unprecedented number of hsr insertion sites. Local chromosome shattering involving a single-step catastrophic event (chromothripsis) was recently proposed to explain clustered chromosomal rearrangements and genomic amplifications in cancer. Our bioinformatics analyses based on the listed criteria to define chromothripsis led us to exclude it as the driving force underlying amplicon genesis in our samples. Instead, the finding of coexisting heterogeneous amplicons, differing in their complexity and chromosome content, in cell lines derived from the same tumor indicated the occurrence of a multi-step evolutionary process in the genesis of dmin/hsr. Our integrated approach allowed us to gather a complete view of the complex chromosome rearrangements occurring within MYC amplicons, suggesting that more than one model may be invoked to explain the origin of dmin/hsr in cancer. Finally, we identified PVT1 as a target of fusion events, confirming its role as breakpoint hotspot in MYC amplification.

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“…The multiple focal amplifications can be either extrachromosomal (double minutes) or intrachromosomal (homogeneously staining regions [HSRs]) due to chromosomal integration of double minutes (Storlazzi et al 2010;Gibaud et al 2013). Indeed, data linking the formation of double minutes to the formation of derivative chromosomes containing complex rearrangements were known prior to the first description of chromothripsis.…”

Section: Does Chromothripsis Cause Cancer?mentioning

confidence: 99%

Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

2013

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Recent genome sequencing studies have identified several classes of complex genomic rearrangements that appear to be derived from a single catastrophic event. These discoveries identify ways that genomes can be altered in single large jumps rather than by many incremental steps. Here we compare and contrast these phenomena and examine the evidence that they arise “all at once.” We consider the impact of massive chromosomal change for the development of diseases such as cancer and for evolution more generally. Finally, we summarize current models for underlying mechanisms and discuss strategies for testing these models.

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Characterization at nucleotide resolution of the homogeneously staining region sites of insertion in two cancer cell lines

Cited by 14 publications

References 37 publications

Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate‐resistant colon cancer cells

Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate‐resistant colon cancer cells

Genomic organization and evolution of double minutes/homogeneously staining regions withMYCamplification in human cancer

Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements

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