Abstract
: Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol η) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol η displays significant protein induction and forms intense foci throughout the nucleus in response to replication stress induced by drugs that do not directly form DNA adducts. During replication stress, Pol η-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol η-deficient cells continue to display aberrant phenotypes, including delayed cell-cycle progression, apoptosis, and cell survival. Depletion or inhibition of ATR was synthetically lethal with Pol η deficiency, particularly when tumor cells were treated with replication stress-inducing drugs. Together our data expand knowledge of the cellular environments that increase endogenous Pol η expression beyond DNA damaging agents and demonstrate that Pol η regulation is central to the replication stress response. Because Pol η is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol η and ATR as a potential therapeutic strategy. SIGNIFICANCE: This study demonstrates that replication stress upregulates Pol η (POLH) in tumor cells and reveals a role for Pol η in tumor cell recovery following replication stress.
Highlights
DNA polymerase eta (Pol h; POLH gene) is a DNA polymerase belonging to a subset of tumor suppressor proteins required for maintaining genome integrity
In response to DNA damage, human Pol h is relocalized to replication foci, where it functions in translesion synthesis (TLS) through a pathway requiring Rad18 [5, 6]
Pol h expression is upregulated during replication stress We sought to understand the pathologic conditions leading to increased expression of endogenous Pol h, as has been reported in therapy na€ve head and neck squamous cell carcinomas (HNSCC) and non–small cell lung carcinomas (NSCLC) tumors [23, 24]
Summary
DNA polymerase eta (Pol h; POLH gene) is a DNA polymerase belonging to a subset of tumor suppressor proteins required for maintaining genome integrity. Homozygous mutation of POLH results in the human cancer predisposition syndrome xeroderma pigmentosum variant 1, 2), and Pol h-deficient mice have an increased incidence of UV-induced skin cancer [3]. Pol h is a specialized DNA polymerase, classically studied in the DNA damage response, due to its unique capacity to accurately bypass the major UV lesion [4]. In response to DNA damage, human Pol h is relocalized to replication foci, where it functions in translesion synthesis (TLS) through a pathway requiring Rad18 [5, 6]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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