Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress
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Mary E. Gagou1, Anil Ganesh1, Geraldine Phear1, Darren Robinson2, Eva Petermann3, Angela Cox1, Mark Meuth1
1Academic Unit of Molecular Oncology, Department of Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK
2Light Microscopy Facility, Department of Biomedical Science, University of Sheffield, Firth Court, Sheffield, UK
3School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, UK
Mary E. Gagou, e-mail: [email protected]
Mark Meuth, e-mail: [email protected]
Keywords: helicases, replication stress, oncogenes, human cells
Received: July 23, 2014 Accepted: September 16, 2014 Published: November 05, 2014
Unwinding duplex DNA is a critical processing step during replication, repair and transcription. Pif1 are highly conserved non-processive 5′->3′ DNA helicases with well-established roles in maintenance of yeast genome stability. However, the function of the sole member of Pif1 family in humans remains unclear. Human PIF1 is essential for tumour cell viability, particularly during replication stress, but is dispensable in non-cancerous cells and Pif1 deficient mice. Here we report that suppression of PIF1 function slows replication fork rates and increases arrested forks during normal cycling conditions. Importantly, PIF1-dependent replication impediments impair S-phase progression and reduce proliferation rates of RAS oncogene-transformed fibroblasts, where replication fork slowing is exacerbated, but not parental, non-cancerous cells. Disrupted fork movement upon PIF1-depletion does not enhance double-stranded break formation or DNA damage responses but affects resumption of DNA synthesis after prolonged replication inhibitor exposure, accompanied by diminished new origin firing and mainly S-phase entry. Taken together, we characterised a functional role for human PIF1 in DNA replication that becomes important for cell growth under oncogenic stress. Given that oncogenes induce high levels of replication stress during the early stages of tumorigenesis, this function of PIF1 could become critical during cancer development.
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