DNA polymerase zeta is required for proliferation of normal mammalian cells.

ABSTRACT: Unique among translesion synthesis (TLS) DNA polymerases, pol ? is essential during embryogenesis. To determine whether pol ? is necessary for proliferation of normal cells, primary mouse fibroblasts were established in which Rev3L could be conditionally inactivated by Cre recombinase. Cells were grown in 2% O(2) to prevent oxidative stress-induced senescence. Cells rapidly became senescent or apoptotic and ceased growth within 3-4 population doublings. Within one population doubling following Rev3L deletion, DNA double-strand breaks and chromatid aberrations were found in 30-50% of cells. These breaks were replication dependent, and found in G1 and G2 phase cells. Double-strand breaks were reduced when cells were treated with the reactive oxygen species scavenger N-acetyl-cysteine, but this did not rescue the cell proliferation defect, indicating that several classes of endogenously formed DNA lesions require Rev3L for tolerance or repair. T-antigen immortalization of cells allowed cell growth. In summary, even in the absence of external challenges to DNA, pol ? is essential for preventing replication-dependent DNA breaks in every division of normal mammalian cells. Loss of pol ? in slowly proliferating mouse cells in vivo may allow accumulation of chromosomal aberrations that could lead to tumorigenesis. Pol ? is unique amongst TLS polymerases for its essential role in cell proliferation.

SUBMITTER: Lange SS 

PROVIDER: S-EPMC3378892 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other