Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

MaryClare F Rollins; Dana M van der Heide; Carla M Weisend; Jean A Kundert; Kristin M Comstock; Elena S Suvorova; Mario R Capecchi; Gary F Merrill; Edward E Schmidt

doi:10.1242/jcs.068106

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Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

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Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration

MaryClare F Rollins, Dana M van der Heide, Carla M Weisend, Jean A Kundert, Kristin M Comstock, Elena S Suvorova, Mario R Capecchi, Gary F Merrill and Edward E Schmidt

Journal of cell science, Vol.123(14), pp.2402-2412

07/15/2010

DOI: https://doi.org/10.1242/jcs.068106

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https://hdl.handle.net/2376/104112

PMCID: PMC2894656

PMID: 20571049

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Abstract

Ribonucleotide reductase

DNA precursors

Cell cycle

Replication

Proliferation

Partial hepatectomy

Liver regeneration

Cells require ribonucleotide reductase (RNR) activity for DNA replication. In bacteria, electrons can flow from NADPH to RNR by either a thioredoxin-reductase- or a glutathione-reductase-dependent route. Yeast and plants artificially lacking thioredoxin reductases exhibit a slow-growth phenotype, suggesting glutathione-reductase-dependent routes are poor at supporting DNA replication in these organisms. We have studied proliferation of thioredoxin-reductase-1 (Txnrd1)-deficient hepatocytes in mice. During development and regeneration, normal mice and mice having Txnrd1-deficient hepatocytes exhibited similar liver growth rates. Proportions of hepatocytes that immunostained for PCNA, phosphohistone H3 or incorporated BrdU were also similar, indicating livers of either genotype had similar levels of proliferative, S and M phase hepatocytes, respectively. Replication was blocked by hydroxyurea, confirming that RNR activity was required by Txnrd1-deficient hepatocytes. Regenerative thymidine incorporation was similar in normal and Txnrd1-deficient livers, further indicating that DNA synthesis was unaffected. Using genetic chimeras in which a fluorescently marked subset of hepatocytes was Txnrd1-deficient while others were not, we found that the multigenerational contributions of both hepatocyte types to development and to liver regeneration were indistinguishable. We conclude that, in mouse hepatocytes, a Txnrd1-independent route for the supply of electrons to RNR can fully support DNA replication and normal proliferative growth.

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Title: Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration
Creators: MaryClare F Rollins - Veterinary Molecular Biology, Montana State University
Dana M van der Heide - Biology Department, Oberlin College
Carla M Weisend - Veterinary Molecular Biology, Montana State University
Jean A Kundert - Animal Resources Center, Montana State University
Kristin M Comstock - Biology Department, The College of St Scolastica
Elena S Suvorova - Veterinary Molecular Biology, Montana State University
Mario R Capecchi - Howard Hughes Medical Institute, University of Utah
Gary F Merrill - Department of Biochemistry and Biophysics, Oregon State University
Edward E Schmidt - Veterinary Molecular Biology, Montana State University
Publication Details: Journal of cell science, Vol.123(14), pp.2402-2412
Academic Unit: UNKNOWN
Publisher: Company of Biologists
Identifiers: 99900546965601842
Language: English
Resource Type: Journal article