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RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures.
- Source :
-
Cell cycle (Georgetown, Tex.) [Cell Cycle] 2012 Nov 15; Vol. 11 (22), pp. 4252-65. Date of Electronic Publication: 2012 Oct 24. - Publication Year :
- 2012
-
Abstract
- RECQ1 is the most abundant of the five human RecQ helicases, but little is known about its biological significance. Recent studies indicate that RECQ1 is associated with origins of replication, suggesting a possible role in DNA replication. However, the functional role of RECQ1 at damaged or stalled replication forks is still unknown. Here, for the first time, we show that RECQ1 promotes strand exchange on synthetic stalled replication fork-mimicking structures and comparatively analyze RECQ1 with the other human RecQ helicases. RECQ1 actively unwinds the leading strand of the fork, similar to WRN, while RECQ4 and RECQ5β can only unwind the lagging strand of the replication fork. Human replication protein A modulates the strand exchange activity of RECQ1 and shifts the equilibrium more to the unwinding mode, an effect also observed for WRN. Stable depletion of RECQ1 affects cell proliferation and renders human cells sensitive to various DNA damaging agents that directly or indirectly block DNA replication fork progression. Consequently, loss of RECQ1 activates DNA damage response signaling, leads to hyper-phosphorylation of RPA32 and activation of CHK1, indicating replication stress. Furthermore, depletion of RECQ1 leads to chromosomal condensation defects and accumulation of under-condensed chromosomes. Collectively, our observations provide a new insight into the role of RECQ1 in replication fork stabilization and its role in the DNA damage response to maintain genomic stability.
- Subjects :
- Cell Line, Tumor
Chromosomes metabolism
DNA chemistry
DNA metabolism
DNA Damage drug effects
Exodeoxyribonucleases genetics
Exodeoxyribonucleases metabolism
Exodeoxyribonucleases pharmacology
HeLa Cells
Humans
RNA Interference
RNA, Small Interfering metabolism
RecQ Helicases antagonists & inhibitors
RecQ Helicases genetics
RecQ Helicases pharmacology
Recombinant Proteins biosynthesis
Recombinant Proteins genetics
Recombinant Proteins pharmacology
Replication Protein A genetics
Replication Protein A metabolism
Replication Protein A pharmacology
Signal Transduction drug effects
Werner Syndrome Helicase
DNA Replication
RecQ Helicases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1551-4005
- Volume :
- 11
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Cell cycle (Georgetown, Tex.)
- Publication Type :
- Academic Journal
- Accession number :
- 23095637
- Full Text :
- https://doi.org/10.4161/cc.22581