Fig. 7: A hypothetical model depicting how SPOP mutation impairs DNA replication and sensitizes cancer cells to ATR inhibition. | Nature Communications

Fig. 7: A hypothetical model depicting how SPOP mutation impairs DNA replication and sensitizes cancer cells to ATR inhibition.

From: SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition

Fig. 7

a SPOP-CUL3-RBX1 functions as an E3 ubiquitin ligase that binds to Geminin and catalyzes K27-linked poly-ubiquitination of Geminin at Lys100 and Lys127. b SPOP-dependent Geminin poly-ubiquitination blocks Cdt1 binding to MCM proteins. Poly-ubiquitination keeps the licensing-competent state in check and prevents DNA replication over-firing. c Cancer-associated SPOP mutations impair DNA replication surveillance and cause replication origin over-firing and re-replication. d SPOP mutations trigger replication catastrophe and cancer cell death upon ATR inhibition.

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