- R loops, which arise from stable DNA:RNA hybrids during transcription, are a major source of genomic instability; they often "collide" with DNA replication forks, impeding the progression of the forks and resulting in DNA double-stranded breaks
- The ATR kinase, the key responder to a broad spectrum of DNA damage and DNA replication problems in human cells, responds to DNA replication forks stalled by R loops, and functions with the effector kinase Chk1 to protect the genome
- This study showed that the ATR-Chk1 pathway is activated by R loops through the action of MUS81, an endonuclease, and that ATR "fine tunes" MUS81 activity to prevent excessive cleavage of reversed forks
- In addition, ATR suppresses DNA double-stranded break formation and enforces checkpoint arrest
- ATR inhibition might prove highly effective in selectively killing cancer cells that harbor high levels of R loops
The ATR kinase is the key responder to a broad spectrum of DNA damage and DNA replication problems. In many cancers, tumor cells have increased dependence on ATR signaling for survival.
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Lee Zou, PhD, associate scientific director of the Massachusetts General Hospital Cancer Center, and colleagues at the Mass General Cancer Center have added to the understanding of ATR as a potential target for cancer therapy. In Molecular Cell, they report ATR protects the genome against R loops, which suggests ATR inhibition may selectively kill cancer cells harboring high levels of R loops.
Background on R Loops
During transcription, newly formed RNA can hybridize with the DNA template, producing a three-stranded structure—an R loop. In cancer cells, R loops often accumulate at excessive levels, leading to genomic instability and DNA damage.
R loops often "collide" with DNA replication forks, impeding the progression of the forks and resulting in DNA double-stranded breaks. ATR responds to R loops and acts with the effector kinase Chk1 to protect the genome. However, until now it wasn't known how ATR is activated by R loops or exactly how it responds.
The New Findings
Mass General researchers have developed novel biochemical and cell biological assays to investigate the process of ATR activation. In this study they found that:
- The collision of R loops and replication forks induces fork reversal, and the ATR-Chk1 pathway is activated by R loops through the action of MUS81, an endonuclease, on reversed forks
- ATR "fine tunes" MUS81 activity, preventing excessive cleavage of reversed forks by MUS81
- In addition to promoting replication fork recovery, ATR suppresses DNA double-stranded break formation and enforces checkpoint arrest
This study establishes that ATR is important not only for sensing DNA damage and replication stress but also as a key sensor and suppressor of transcription-derived genomic instability. Most excitingly, the findings suggest inhibiting ATR and perhaps other molecules involved in suppressing R loop accumulation could prove highly effective as cancer therapies.
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