DNA polymerase eta prevents tumor cell-cycle arrest and cell death during recovery from replication stress

Ryan P. Barnes, Wei Chung Tsao, George-Lucian Moldovan, Kristin Eckert

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 h) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol h 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 h-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol h-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 h 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 h expression beyond DNA damaging agents and demonstrate that Pol h regulation is central to the replication stress response. Because Pol h is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol h and ATR as a potential therapeutic strategy. Significance: This study demonstrates that replication stress upregulates Pol h (POLH) in tumor cells and reveals a role for Pol h in tumor cell recovery following replication stress.

Original languageEnglish (US)
Pages (from-to)6549-6560
Number of pages12
JournalCancer Research
Volume78
Issue number23
DOIs
StatePublished - Dec 1 2018

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Cell Cycle Checkpoints
Cell Death
Neoplasms
Genomic Instability
Cell Survival
Cell Cycle
DNA Adducts
Protein Transport
DNA Replication
Pharmaceutical Preparations
Rad30 protein
Up-Regulation
Apoptosis
Phenotype
Drug Therapy
DNA
Enzymes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "DNA polymerase eta prevents tumor cell-cycle arrest and cell death during recovery from replication stress",
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 h) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol h 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 h-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol h-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 h 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 h expression beyond DNA damaging agents and demonstrate that Pol h regulation is central to the replication stress response. Because Pol h is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol h and ATR as a potential therapeutic strategy. Significance: This study demonstrates that replication stress upregulates Pol h (POLH) in tumor cells and reveals a role for Pol h in tumor cell recovery following replication stress.",
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DNA polymerase eta prevents tumor cell-cycle arrest and cell death during recovery from replication stress. / Barnes, Ryan P.; Tsao, Wei Chung; Moldovan, George-Lucian; Eckert, Kristin.

In: Cancer Research, Vol. 78, No. 23, 01.12.2018, p. 6549-6560.

Research output: Contribution to journalArticle

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