TY - JOUR

T1 - A Link between Deoxyribonucleotide Metabolites and Embryonic Cell-Cycle Control

AU - Liu, B.

AU - Winkler, F.

AU - Herde, M.

AU - Witte, C.-P.

AU - Großhans, J.

N1 - Funding Information: We thank S. Blythe, B. Loppin, M. Niehaus, C. Rushlow, S. Shvartsman, E. Wieschaus, N. Zielke, and the Bloomington Drosophila Stock Center supported by NIH P40OD018537 for discussions, materials, and fly stocks. B.L. was in part supported by a fellowship from the China Scholarship Council (CSC). This work was in part supported by the Göttingen Center for Molecular Biology (equipment repair funds) and the Deutsche Forschungsgemeinschaft (GR1945/3-1 to J.G. HE5949/3-1 to M.H. and equipment grant INST1525/16-1 FUGG to J.G.). B.L. and F.W. conducted the experimental work and analyzed the data, J.G. conceived the project and conducted initial phenotype analysis and genetic mapping, J.G. and B.L. wrote the manuscript, and M.H. and C.-P.W. conducted the analytical dNTP measurements. The authors declare no competing interests.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - The egg contains maternal RNAs and proteins, which have instrumental functions in patterning and morphogenesis. Besides these, the egg also contains metabolites, whose developmental functions have been little investigated. For example, the rapid increase of DNA content during the fast embryonic cell cycles poses high demands on the supply of deoxyribonucleotides (dNTPs), which may be synthesized in the embryo or maternally provided [1, 2]. Here, we analyze the role of dNTP in early Drosophila embryos. We found that dNTP levels initially decreased about 2-fold before reaching stable levels at the transition from syncytial to cellular blastoderm. Employing a mutant of the metabolic enzyme serine hydroxymethyl transferase (SHMT), which is impaired in the embryonic synthesis of deoxythymidine triphosphate (dTTP), we found that the maternal supply of dTTP was specifically depleted by interphase 13. SHMT mutants showed persistent S phase, replication stress, and a checkpoint-dependent cell-cycle arrest in NC13, depending on the loss of dTTP. The cell-cycle arrest in SHMT mutants was suppressed by reduced zygotic transcription. Consistent with the requirement of dTTP for cell-cycle progression, increased dNTP levels accelerated the cell cycle in embryos lacking zygotic transcription. We propose a model that both a limiting dNTP supply and interference of zygotic transcription with DNA replication [3] elicit DNA replication stress and checkpoint activation. Our study reveals a specific mechanism of how dNTP metabolites contribute to the embryonic cell-cycle control. Liu et al. show that dNTP metabolites contribute to cell-cycle control in Drosophila embryos in parallel to zygotic transcription. Embryos deficient for de novo dTTP synthesis activate the DNA checkpoint and arrest in interphase 13, whereas experimentally increased dNTP levels accelerate the cell cycle in embryos lacking zygotic transcription.

AB - The egg contains maternal RNAs and proteins, which have instrumental functions in patterning and morphogenesis. Besides these, the egg also contains metabolites, whose developmental functions have been little investigated. For example, the rapid increase of DNA content during the fast embryonic cell cycles poses high demands on the supply of deoxyribonucleotides (dNTPs), which may be synthesized in the embryo or maternally provided [1, 2]. Here, we analyze the role of dNTP in early Drosophila embryos. We found that dNTP levels initially decreased about 2-fold before reaching stable levels at the transition from syncytial to cellular blastoderm. Employing a mutant of the metabolic enzyme serine hydroxymethyl transferase (SHMT), which is impaired in the embryonic synthesis of deoxythymidine triphosphate (dTTP), we found that the maternal supply of dTTP was specifically depleted by interphase 13. SHMT mutants showed persistent S phase, replication stress, and a checkpoint-dependent cell-cycle arrest in NC13, depending on the loss of dTTP. The cell-cycle arrest in SHMT mutants was suppressed by reduced zygotic transcription. Consistent with the requirement of dTTP for cell-cycle progression, increased dNTP levels accelerated the cell cycle in embryos lacking zygotic transcription. We propose a model that both a limiting dNTP supply and interference of zygotic transcription with DNA replication [3] elicit DNA replication stress and checkpoint activation. Our study reveals a specific mechanism of how dNTP metabolites contribute to the embryonic cell-cycle control. Liu et al. show that dNTP metabolites contribute to cell-cycle control in Drosophila embryos in parallel to zygotic transcription. Embryos deficient for de novo dTTP synthesis activate the DNA checkpoint and arrest in interphase 13, whereas experimentally increased dNTP levels accelerate the cell cycle in embryos lacking zygotic transcription.

KW - DNA checkpoint

KW - Drosophila

KW - RNR

KW - SHMT

KW - blastoderm

KW - cell cycle

KW - deoxyribonucleotide metabolism

KW - haploid

KW - replication stress

KW - zygotic transcription

UR - http://www.scopus.com/inward/record.url?scp=85063351310&partnerID=8YFLogxK

U2 - 10.15488/17927

DO - 10.15488/17927

M3 - Article

VL - 29

SP - 1187-1192.e3

JO - Current biology

JF - Current biology

SN - 0960-9822

IS - 7

ER -