平成27年度 医学研セミナー

Molecular mechanisms of DNA replication errors under replication stresses and the subsequent chromosome instability.

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演者 水野 健一 博士(英国サセックス大学Genome Damage & Stability Centre )
会場 東京都医学総合研究所 2階講堂
日時 平成27年7月2日(木) 16:30 ~ 17:30 ←時間が変更になりました
世話人 正井 久雄 副所長
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Impediment to DNA replication often results in gross chromosomal rearrangements linked to cancer development and neurological conditions. However, the molecular mechanism of genome instability that results from DNA replication impediment remains unclear. We have developed systems in fission yeast to arrest a replication fork at a specific site in genome exploiting a replication fork terminator sequence RTS1. We have previously shown that an arrested fork at RTS1 restarts in a manner dependent on homologous recombination (HR). HR helps the arrested forks restart using original template DNA or occasionally a homologous sequence nearby as template. This Non-Allelic Homologous Recombination (NAHR) results in chromosomal rearrangement. In addition, we showed that chromosome rearrangements arise by a novel mechanism when the fork restarted by HR on the original template, U-turns at inverted repeats. Thus, HR-restated forks are non-canonical and error prone. The chromosomal rearrangements are reciprocal sister chromatid fusions, generating dicentric and acentric chromosomes. The dicentric forms a bridge causing catastrophic mitosis and chromosome breakage. This observation is relevant to common fragile sites in mammalian cells, which show mitotic defects such as chromosome bridges and chromatid breaks under replication stresses.