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DNA Cross-Linker-Induced G2/M Arrest in Group C Fanconi Anemia
Lymphoblasts Reflects Normal Checkpoint Function
Michael C. Heinrich,
Maureen E. Hoatlin,
Amy J. Zigler,
Kirsten V. Silvey,
Antony C. Bakke,
Winifred W. Keeble,
Yu Zhi,
Carol A. Reifsteck,
Markus Grompe,
Michael G. Brown,
R. Ellen Magenis,
Susan
B. Olson, and
Grover C. Bagby Jr
From the Division of Hematology and Medical Oncology, Department of
Medicine, the Department of Molecular and Medical Genetics, and the
Department of Pediatrics, Oregon Health Sciences University; and
Portland Veterans Affairs Medical Center, Portland, OR.
Cells from individuals with Fanconi anemia (FA) arrest excessively
in the G2/M cell cycle compartment after exposure to low doses of DNA
cross-linking agents. The relationship of this abnormality to the
fundamental genetic defect in such cells is unknown, but many
investigators have speculated that the various FA genes directly regulate cell cycle checkpoints. We tested the hypothesis that the
protein encoded by the FA group C complementing gene (FAC) functions to control a cell cycle checkpoint and that cells from group
C patients (FA[C]) have abnormalities of cell cycle regulation directly related to the genetic mutation. We found that retroviral transduction of FA(C) lymphoblasts with wild-type FAC cDNA
resulted in normalization of the cell cycle response to low-dose
mitomycin C (MMC). However, when DNA damage was quantified in terms of
cytogenetic damage or cellular cytotoxicity, we found similar degrees
of G2/M arrest in response to equitoxic amounts of MMC in FA(C) cells as well as in normal lymphoblasts. Similar results were obtained using
isogenic pairs of uncorrected, FAC- or mock-corrected (neo only) FA(C) cell lines. To test the function of other checkpoints we
examined the effects of hydroxyurea (HU) and ionizing radiation on cell
cycle kinetics of FA(C) and normal lymphoblasts as well as with
isogenic pairs of uncorrected, FAC-corrected, or mock-corrected FA(C)
cell lines. In all cases the cell cycle response of FA(C) and normal
lymphoblasts to these two agents were identical. Based on these studies
we conclude that the aberrant G2/M arrest that typifies the response of
FA(C) cells to low doses of cross-linking agents does not represent an
abnormal cell cycle response but instead represents a normal cellular
response to the excessive DNA damage that results in FA(C) cells
following exposure to low doses of cross-linking agents.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 275-287
© 1998 by The American Society of Hematology.
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