Levels Of dNTP Levels After DNA Damage Regulates Translesion Bypass Response - Genome Dynamics in Neuroscience and Aging

Claus Desler ¹ Thomas Lau Hansen ¹ Rui She ¹ Kristina Schmidt ² Lene Juel Rasmussen ¹

¹Department of Cellular and Molecular Medicine, University of Copenhagen, Center for Healthy Aging, Denmark
²Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, USA

Genomic instability is a hallmark of aging. Translesion synthesis (TLS) is the process by which DNA lesions are bypassed by incorporation of a nucleotide opposite to the lesion. In both S. cerevisiae and E. coli, DNA lesions that block DNA replication have been demonstrated to result in a 6-8 fold increase in levels of deoxyribonucleotide triphosphates (dNTP). The increase of dNTP levels is essential for cell survival following treatment with DNA damaging agents and proposed to be linked to TLS.

With this work, we show that the level of dNTP is an important regulator of the TLS response and we demonstrate that a restricted synthesis of dNTP, inhibits yeast cells usage of the TLS Pol ζ but not TLS Pol η as the primary TLS polymerase when bypassing bulky DNA adducts. Furthermore, we show that this restriction causes a significant increase of chromosomal aberrations.

We believe a similar regulatory mechanism of the TLS response exists in human cells in which DNA damage sites results in the formation of a microenvironment where the dNTP levels are increased in a similar fashion as in yeast cells after DNA damage.