AI Article Synopsis
- Overexpression of the flap endonuclease FEN1 and its homolog RAD27 in yeast leads to impaired DNA replication, causing cells to accumulate in mid-S phase.
- This overexpression results in heightened activity of checkpoint kinases and sensitivity to DNA-damaging agents, indicating a link to genome instability.
- The adverse effects of RAD27 overexpression can be mitigated by disrupting its interaction with the replication clamp PCNA, highlighting its role in replication-related damage.
Article Abstract
Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129. RAD27 overexpressing cells were hypersensitive to treatment with DNA damaging agents, and defective in ubiquitinating the replication clamp proliferating cell nuclear antigen (PCNA) at lysine 164. These effects were reversed when the interaction between overexpressed Rad27 and PCNA was ablated, suggesting that the observed phenotypes were linked to problems in DNA replication. RAD27 overexpressing cells also exhibited an unexpected dependence on the SUMO ligases SIZ1 and MMS21 for viability. Importantly, we found that overexpression of FEN1 in human cells also led to phosphorylation of CHK1, CHK2, RPA32 and histone H2AX, all markers of genome instability. Our data indicate that flap endonuclease overexpression is a driver of genome instability in yeast and human cells that impairs DNA replication in a manner dependent on its interaction with PCNA.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009675 | PMC |
| http://dx.doi.org/10.1093/nar/gky313 | DOI Listing |
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