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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Understanding and Targeting R Loops in Cancer Cells

R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Our recent studies have suggested that ATR is involved in the sensing of R loops. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In response to aberrant R loop accumulation, the ATR-Chk1 pathway is activated by R loop-induced reversed replication forks. ATR protects the genome from R loops by suppressing transcription-replication collisions, promoting replication fork recovery, and enforcing a G2/M cell-cycle arrest. Furthermore, ATR prevents excessive cleavage of reversed forks by MUS81. These results suggest that ATR is a key sensor and suppressor of R loop-induced genomic instability, uncovering a signaling circuitry that safeguards the genome against R loops.

We also find that ATR is important for survival of cancer cells harboring high levels of R loops. Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of myelodysplastic syndrome (MDS) and AML patients. We show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops and elicits an ATR response. ATR inhibitors (ATRi) induced DNA damage and cell death in U2AF1S34F-expressing cells, and these effects of ATRi were enhanced by splicing modulating compounds. Our results suggest that ATR may represent a novel therapeutic target in MDS patients carrying the U2AF1(S34F) mutation and potentially other malignancies harboring spliceosome mutations.

Lee Zou 1,2

1Massachusetts General Hospital Cancer Center
2Department of Pathology
Harvard Medical School
Boston, MA

Email: LZOU1@mgh.harvard.edu