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.
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.
|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|