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CstF-64 supports pluripotency and regulates cell cycle progression in embryonic stem cells through histone 3' end processing.

Youngblood BA, Grozdanov PN, MacDonald CC - Nucleic Acids Res. (2014)

Bottom Line: Similarly, the role of 3' end processing in regulation of ESC pluripotency and cell cycle is poorly understood.However, τCstF-64 only partially compensates for lost CstF-64 function, despite being recruited to the histone mRNA 3' end-processing complex.Reduction of τCstF-64 in CstF-64-deficient ESCs results in even greater levels of histone mRNA polyadenylation, suggesting that both CstF-64 and τCstF-64 function to inhibit polyadenylation of histone mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430-6540, USA.

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Schematic representation of how depletion of CstF-64 increases polyadenylation of replication-dependent histone mRNAs and modulates the cell cycle in ESCs and therefore pluripotency. The panel on the left describes the histone mRNA 3′ end processing complex in wild type ESCs. On the right: modified histone mRNA 3′ end processing complex in the Cstf2E6 (CstF-64 knockout) cells. Histone mRNA cleavage occurs in wild type mouse ESCs due to interactions of the U7 snRNP with the histone mRNA downstream element (left panel). Other proteins involved in mRNA polyadenylation further associate with the complex, including CstF-64 and symplekin. The complex promotes site-specific cleavage of the histone mRNA by CPSF-73. Together, these processes correlate with normal entry into S-phase and pluripotency. In normal ESCs, a small amount of these cleaved transcripts are polyadenylated. In Cstf2E6 cells (right panel), CstF-64 is absent, resulting in recruitment of τCstF-64 to the histone 3′ end processing complex (although τCstF-64 interacts more poorly with symplekin). This results in an increase in polyadenylation of the cleaved histone transcripts, presumably by poly(A) polymerase (PAP).
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Figure 7: Schematic representation of how depletion of CstF-64 increases polyadenylation of replication-dependent histone mRNAs and modulates the cell cycle in ESCs and therefore pluripotency. The panel on the left describes the histone mRNA 3′ end processing complex in wild type ESCs. On the right: modified histone mRNA 3′ end processing complex in the Cstf2E6 (CstF-64 knockout) cells. Histone mRNA cleavage occurs in wild type mouse ESCs due to interactions of the U7 snRNP with the histone mRNA downstream element (left panel). Other proteins involved in mRNA polyadenylation further associate with the complex, including CstF-64 and symplekin. The complex promotes site-specific cleavage of the histone mRNA by CPSF-73. Together, these processes correlate with normal entry into S-phase and pluripotency. In normal ESCs, a small amount of these cleaved transcripts are polyadenylated. In Cstf2E6 cells (right panel), CstF-64 is absent, resulting in recruitment of τCstF-64 to the histone 3′ end processing complex (although τCstF-64 interacts more poorly with symplekin). This results in an increase in polyadenylation of the cleaved histone transcripts, presumably by poly(A) polymerase (PAP).

Mentions: We found that CstF-64 interacts more strongly with symplekin than does τCstF-64 (Figure 6D) (24). Others have shown that the CstF-64/symplekin interaction is essential to link FLASH and Lsm11 with the other CPSF factors in the histone mRNA 3′ end-processing complex (15,18). Based on these data, we propose a model in which interaction of CstF-64 with symplekin inhibits the polyadenylation of replication-dependent histone mRNAs in wild type ESCs, supporting both pluripotency and progression through the histone cell cycle checkpoint into S phase while suppressing differentiation. Our data also demonstrate a stronger recruitment of certain CPSF and CstF factors to the replication-dependent histone mRNA 3′ end processing complex in the absence of CstF-64, including CPSF-100, CPSF-160 and CstF-77 (Figure 6A). The increased recruitment of these factors in the Cstf2E6 cells could result in a U7 snRNP complex that favors polyadenylation of histone mRNAs instead of the usual histone stem loop processing (Figure 7).


CstF-64 supports pluripotency and regulates cell cycle progression in embryonic stem cells through histone 3' end processing.

Youngblood BA, Grozdanov PN, MacDonald CC - Nucleic Acids Res. (2014)

Schematic representation of how depletion of CstF-64 increases polyadenylation of replication-dependent histone mRNAs and modulates the cell cycle in ESCs and therefore pluripotency. The panel on the left describes the histone mRNA 3′ end processing complex in wild type ESCs. On the right: modified histone mRNA 3′ end processing complex in the Cstf2E6 (CstF-64 knockout) cells. Histone mRNA cleavage occurs in wild type mouse ESCs due to interactions of the U7 snRNP with the histone mRNA downstream element (left panel). Other proteins involved in mRNA polyadenylation further associate with the complex, including CstF-64 and symplekin. The complex promotes site-specific cleavage of the histone mRNA by CPSF-73. Together, these processes correlate with normal entry into S-phase and pluripotency. In normal ESCs, a small amount of these cleaved transcripts are polyadenylated. In Cstf2E6 cells (right panel), CstF-64 is absent, resulting in recruitment of τCstF-64 to the histone 3′ end processing complex (although τCstF-64 interacts more poorly with symplekin). This results in an increase in polyadenylation of the cleaved histone transcripts, presumably by poly(A) polymerase (PAP).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4117776&req=5

Figure 7: Schematic representation of how depletion of CstF-64 increases polyadenylation of replication-dependent histone mRNAs and modulates the cell cycle in ESCs and therefore pluripotency. The panel on the left describes the histone mRNA 3′ end processing complex in wild type ESCs. On the right: modified histone mRNA 3′ end processing complex in the Cstf2E6 (CstF-64 knockout) cells. Histone mRNA cleavage occurs in wild type mouse ESCs due to interactions of the U7 snRNP with the histone mRNA downstream element (left panel). Other proteins involved in mRNA polyadenylation further associate with the complex, including CstF-64 and symplekin. The complex promotes site-specific cleavage of the histone mRNA by CPSF-73. Together, these processes correlate with normal entry into S-phase and pluripotency. In normal ESCs, a small amount of these cleaved transcripts are polyadenylated. In Cstf2E6 cells (right panel), CstF-64 is absent, resulting in recruitment of τCstF-64 to the histone 3′ end processing complex (although τCstF-64 interacts more poorly with symplekin). This results in an increase in polyadenylation of the cleaved histone transcripts, presumably by poly(A) polymerase (PAP).
Mentions: We found that CstF-64 interacts more strongly with symplekin than does τCstF-64 (Figure 6D) (24). Others have shown that the CstF-64/symplekin interaction is essential to link FLASH and Lsm11 with the other CPSF factors in the histone mRNA 3′ end-processing complex (15,18). Based on these data, we propose a model in which interaction of CstF-64 with symplekin inhibits the polyadenylation of replication-dependent histone mRNAs in wild type ESCs, supporting both pluripotency and progression through the histone cell cycle checkpoint into S phase while suppressing differentiation. Our data also demonstrate a stronger recruitment of certain CPSF and CstF factors to the replication-dependent histone mRNA 3′ end processing complex in the absence of CstF-64, including CPSF-100, CPSF-160 and CstF-77 (Figure 6A). The increased recruitment of these factors in the Cstf2E6 cells could result in a U7 snRNP complex that favors polyadenylation of histone mRNAs instead of the usual histone stem loop processing (Figure 7).

Bottom Line: Similarly, the role of 3' end processing in regulation of ESC pluripotency and cell cycle is poorly understood.However, τCstF-64 only partially compensates for lost CstF-64 function, despite being recruited to the histone mRNA 3' end-processing complex.Reduction of τCstF-64 in CstF-64-deficient ESCs results in even greater levels of histone mRNA polyadenylation, suggesting that both CstF-64 and τCstF-64 function to inhibit polyadenylation of histone mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430-6540, USA.

Show MeSH
Related in: MedlinePlus