Genomic instability is a hallmark of cancer. Cancer cells that are genetically unstable are often susceptible to radiation and chemotherapy. Radiation kills cancer cells by inflicting multiple types of DNA damage, including DNA double-stranded breaks (DSBs). Cancer cells defective for DSB repair, such as those carrying BRCA1/2 mutations, are highly sensitive to radiation. BRCA1/2-deficient cells are also sensitive to PARP inhibitors, presenting a new strategy to improve the efficacy of radiation therapy. However, BRCA1-deficient cancer cells often acquire resistance to radiation and PARP inhibitors due to the bypass of BRCA1 in homologous recombination (HR), hindering the treatment of BRCA1-deficient cancers. These findings raised important questions as to how BRCA1-independent HR differs from BRCA1-dependent HR, and whether the radiation and PARP inhibitor resistance of BRCA1-deficient cells can be overcome. Our recent studies on the master checkpoint kinase ATR have provided important clues to these questions. We found that in BRCA1-proficient cells, ATR phosphorylates BRCA1 and controls its downstream functions in HR. Surprisingly, even in BRCA1- deficient cells where the function of BRCA1 is bypassed, ATR is still critical for HR, suggesting a BRCA1- independent role for ATR in the radiation response. Based on these exciting findings, we hypothesize that ATR regulates HR via both BRCA1-dependent and -independent mechanisms. Furthermore, ATR inhibition may be an effective way to overcome the radiation and PARP inhibitor resistance of BRCA-deficient tumors. We propose to: 1) elucidate how ATR regulates HR by phosphorylating BRCA1; 2) reveal how ATR regulates BRCA1-independent HR; and 3) systematically test if ATR inhibitors can be broadly used to overcome the radiation and PARP inhibitor resistance of BRCA-deficient tumors.

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Genomic instability is a hallmark of cancer and an attractive target for therapy. We will investigate how ATR, a master DNA damage-signaling kinase in human cells, regulates the repair of radiation induced DNA breaks. Furthermore, we will explore how to attack specific vulnerabilities of cancer cells by inhibiting ATR.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Oberdoerffer, Philipp
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Massachusetts General Hospital
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Nguyen, Hai Dang; Leong, Wan Yee; Li, Weiling et al. (2018) Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes. Cancer Res 78:5363-5374
Teng, Yaqun; Yadav, Tribhuwan; Duan, Meihan et al. (2018) ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB. Nat Commun 9:4115
Kabeche, Lilian; Nguyen, Hai Dang; Buisson, Rémi et al. (2018) A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science 359:108-114
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Yazinski, Stephanie A; Comaills, Valentine; Buisson, Rémi et al. (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31:318-332
Ouyang, Jian; Lan, Li; Zou, Lee (2017) Regulation of DNA break repair by transcription and RNA. Sci China Life Sci 60:1081-1086
Buisson, Rémi; Lawrence, Michael S; Benes, Cyril H et al. (2017) APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition. Cancer Res 77:4567-4578
Buisson, Rémi; Niraj, Joshi; Rodrigue, Amélie et al. (2017) Coupling of Homologous Recombination and the Checkpoint by ATR. Mol Cell 65:336-346
Wu, Ching-Shyi; Zou, Lee (2016) The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation. J Biol Chem 291:279-90