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Published on: May 14, 2016
The HiNF-P/p220NPAT cell cycle signaling pathway controls nonhistone target genes
Ricardo Medina1, Margaretha van der Deen, Angela Miele-Chamberland
1Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Abstract:
HiNF-P and its cofactor p220(NPAT) are principal factors regulating histone gene expression at the G(1)-S phase cell cycle transition. Here, we have investigated whether HiNF-P controls other cell cycle- and cancer-related genes. We used cDNA microarrays to monitor responsiveness of gene expression to small interfering RNA-mediated depletion of HiNF-P. Candidate HiNF-P target genes were examined for the presence of HiNF-P recognition motifs, in vitro HiNF-P binding to DNA, and in vivo association by chromatin immunoprecipitations and functional reporter gene assays. Of 177 proliferation-related genes we tested, 20 are modulated in HiNF-P-depleted cells and contain putative HiNF-P binding motifs. We validated that at least three genes (i.e., ATM, PRKDC, and CKS2) are HiNF-P dependent and provide data indicating that the DNA damage response is altered in HiNF-P-depleted cells. We conclude that, in addition to histone genes, HiNF-P also regulates expression of nonhistone targets that influence competency for cell cycle progression.
Insights
HiNF-P regulates cell cycle progression by controlling both histone and non-histone genes. This protein impacts DNA damage response, suggesting broader roles in cell cycle control and cancer.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- Cancer Biology
Background:
- HiNF-P and p220(NPAT) are key regulators of histone gene expression during the G1-S cell cycle transition.
- The broader role of HiNF-P in regulating other cell cycle and cancer-related genes remains largely unexplored.
Purpose of the Study:
- To investigate whether HiNF-P controls additional cell cycle and cancer-related genes beyond histone genes.
- To identify and validate novel non-histone HiNF-P target genes and assess their functional impact.
Main Methods:
- Utilized cDNA microarrays to screen gene expression changes upon HiNF-P depletion via small interfering RNA (siRNA).
- Analyzed candidate genes for HiNF-P recognition motifs, in vitro DNA binding, and in vivo association using chromatin immunoprecipitation (ChIP) and reporter gene assays.
Main Results:
- Out of 177 proliferation-related genes, 20 were modulated by HiNF-P depletion and possessed putative binding motifs.
- Validated HiNF-P dependency for at least three genes: ATM, PRKDC, and CKS2.
- Observed alterations in the DNA damage response in HiNF-P-depleted cells.
Conclusions:
- HiNF-P regulates not only histone genes but also non-histone targets crucial for cell cycle progression.
- HiNF-P plays a significant role in the DNA damage response pathway.
- These findings expand the known functions of HiNF-P in cell cycle control and cancer biology.
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