平成26年度 医学研セミナー

NCOA4 transcriptional coactivator inhibits activation of DNA replication origins

− この都医学研セミナーは終了しました。 −

演者 Professore Francesca Carlomagno
Dipartimento di Medicina Molecolare e Biotecnologie Mediche,Universita di Napoli “Federico II(イタリアナポリ大学)
会場 東京都医学総合研究所 講堂
日時 平成26年11月14日(金)11:00
世話人 正井 久雄 参事研究員(ゲノム動態プロジェクト)
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NCOA4 is a coactivator of nuclear receptors such as Androgen Receptor or Estrogen Receptor and undergoes rearrangements in human cancer. We proved that NCOA4 protein controlled CMG activity and DNA replication. By using Xenopus laevis egg extracts and gene targeting in mouse embryonic fibroblasts, we showed that NCOA4 bound to MCM2-7 complex and obstructed DNA helicase activation, thereby reducing the number of active DNA replication origins. This function was independent from its transcriptional activity. Accordingly, NCOA4 ablation in mouse embryonic fibroblasts lead to unscheduled DNA replication and premature senescence due to replication stress. Thus, reduction of activated origins by CDC7 inhibitor PHA-767491 restored normal fork progression. As a regulator of CMG helicase and replication origins, NCOA4 might function in a regulatory circuit that integrates DNA replication and transcription controls. Moreover, this novel pathway may be targeted by cancer driving genetic alterations such as NCOA4 gene rearrangements in thyroid and lung carcinomas.