Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosome(Cdh1) (APC/C(Cdh1)) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C(Cdh1) through degradation of Cdh1 upon replication block, thereby stabilizing APC/C(Cdh1) substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase η. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse under conditions of replication stress.

• Klíčová slova
• APC/CCdh1, Cdc7, Chk1, DNA lesion bypass, RAD18, replication stress,
• MeSH
• ATM protein metabolismus   MeSH
• CD antigeny MeSH
• checkpoint kinasa 1 MeSH
• geny APC fyziologie   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• poškození DNA * MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• replikace DNA * MeSH
• signální transdukce MeSH
• stabilita enzymů MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• CD antigeny MeSH
• CDC7 protein, human MeSH Prohlížeč
• CDH1 protein, human MeSH Prohlížeč
• checkpoint kinasa 1 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• DBF4 protein, human MeSH Prohlížeč
• kadheriny MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasy MeSH
• proteiny buněčného cyklu MeSH