Doctoral thesis

Mechanisms of oncogene-induced DNA replication stress

ContributorsMacheret, Morgane
Defense date2017-04-28

Oncogenes in human cancers induce DNA replication stress and genomic instability. Towards elucidating the underlying molecular mechanisms, we monitored origin firing in human cells after inducibly activating the proto-oncogenes cyclin E or MYC. Both oncogenes led to firing of novel replication origins within highly transcribed genes. These novel origins were normally suppressed by transcription during G1, but precocious entry into S phase allowed origin firing within genomic regions that had not yet been transcribed. Forks from oncogene-induced origins were prone to collapse, due to conflicts between replication and transcription, and were associated with DNA double-strand break formation and chromosomal rearrangement breakpoints. We propose that in normal cells, initiation of DNA replication is mostly restricted to non-transcribed genomic regions, whereas shortening of G1 in cancer cells leads to origin firing within transcribed genes, fork collapse and genomic instability.

Research group
Citation (ISO format)
MACHERET, Morgane. Mechanisms of oncogene-induced DNA replication stress. 2017. doi: 10.13097/archive-ouverte/unige:94383
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Creation05/19/2017 4:02:00 PM
First validation05/19/2017 4:02:00 PM
Update time03/15/2023 1:42:18 AM
Status update03/15/2023 1:42:18 AM
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