E-life誌に新しい論文がacceptされました。

2019年(令和元年)12月31日　E-life誌に新しい論文が採択されました。

Title：Cdc7 activates replication checkpoint by phosphorylating the Chk1 binding domain of Claspin in human cells

Authors：Chi-Chun Yang, Hiroyuki Kato, Mayumi Shindo and Hisao Masai*

Abstract：Replication checkpoint is essential for maintaining genome integrity in response to various replication stresses as well as during the normal growth. The evolutionally conserved ATR-Claspin-Chk1 pathway is induced during replication checkpoint activation. Cdc7 kinase, required for initiation of DNA replication at replication origins, has been implicated in checkpoint activation but how it is involved in this pathway has not been known. Here, we show that Cdc7 is required for Claspin-Chk1 interaction in human cancer cells by phosphorylating CKBD (Chk1-binding-domain) of Claspin. The residual Chk1 activation in Cdc7-depleted cells is lost upon further depletion of casein kinase1 (CK1γ1), previously reported to phosphorylate CKBD. Thus, Cdc7, in conjunction with CK1γ1, facilitates the interaction between Claspin and Chk1 through phosphorylating CKBD. We also show that, whereas Cdc7 is predominantly responsible for CKBD phosphorylation in cancer cells, CK1γ1plays a major role in non-cancer cells, providing rationale for targeting Cdc7 for cancer cell-specific cell killing.

本論文では、ヒトCdc7キナーゼが複製チェックポイントアダプタータンパク質であるClaspinのリン酸化を介してDNA複製チェックポイントを活性化するメカニズムを解明しました。さらにCdc7は、がん細胞において特異的に複製チェックポイントの活性化に関与するのに対して、正常細胞ではCK1γ1キナーゼが主要な役割を果たすことを見出しました。これらの発見は、がん細胞は正常細胞と異なる分子を用いて複製ストレスを制御していることを示し、がん細胞特異的な増殖制御、細胞死誘導のための戦略の可能性を示唆します。