TY - JOUR
T1 - Loss of DNA polymerase ζ causes chromosomal instability in mammalian cells
AU - Wittschieben, John P.
AU - Reshmi, Shalini C.
AU - Gollin, Susanne M.
AU - Wood, Richard D.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - Rev3L encodes the catalytic subunit of DNA polymerase ζ (pol ζ) in mammalian cells. In yeast, pol ζ helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L-/- mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol ζ may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L-/- MEFs on a p53-/- genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and γ-radiation, indicating that mammalian pol ζ helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L -/- MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression.
AB - Rev3L encodes the catalytic subunit of DNA polymerase ζ (pol ζ) in mammalian cells. In yeast, pol ζ helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L-/- mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol ζ may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L-/- MEFs on a p53-/- genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and γ-radiation, indicating that mammalian pol ζ helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L -/- MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression.
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U2 - 10.1158/0008-5472.CAN-05-2982
DO - 10.1158/0008-5472.CAN-05-2982
M3 - Article
C2 - 16397225
AN - SCOPUS:31544434491
SN - 0008-5472
VL - 66
SP - 134
EP - 142
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -