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Expression of E7 proteins encoded by carcinogenic, high-risk human papillomaviruses (HPVs) triggers increased expression of the histone H3 lysine 27 demethylase KDM6A. KDM6A expression is necessary for survival of high-risk HPV E7 expressing cells, including several cervical cancer lines. Here we show that increased KDM6A in response to high-risk HPV E7 expression causes epigenetic de-repression of the cell cycle and DNA replication inhibitor p21 CIP1 , and p21 CIP1  expression is necessary for survival of high-risk HPV E7 expressing cells. The requirement for KDM6A and p21 CIP1  expression for survival of high-risk HPV E7 expressing cells is based on p21 CIP1 ’s ability to inhibit DNA replication through PCNA binding. We show that ectopic expression of cellular replication factors can rescue the loss of cell viability in response to p21 CIP1  and KDM6A depletion. Moreover, we discovered that nucleoside supplementation will override the loss of cell viability in response to p21 CIP1  depletion, suggesting that p21 CIP1  depletion causes lethal replication stress. This model is further supported by increased double strand DNA breaks upon KDM6A or p21 CIP1  depletion and DNA combing experiments that show aberrant re-replication upon KDM6A or p21 CIP1  depletion in high-risk HPV E7 expressing cells. Therefore, KDM6A and p21 CIP1  expression are essential to curb E7 induced replication stress to levels that do not markedly interfere with cell viability.

KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress