Underappreciated Roles of DNA Polymerase δ in Replication Stress Survival

• Published in: Trends in genetics 2021-05, Vol.37 (5), p.476-487
• Main Authors: Fuchs, Jeannette, Cheblal, Anais, Gasser, Susan M.
• Format: Article
• Language: English
• Subjects: cancer mutations; complex stability; DNA Pol δ; DNA polymerases; replication stress
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2020.12.003

Recent structural analysis of Fe-S centers in replication proteins and insights into the structure and function of DNA polymerase δ (DNA Pol δ) subunits have shed light on the key role played by this polymerase at replication forks under stress. The sequencing of cancer genomes reveals multiple point mutations that compromise the activity of POLD1, the DNA Pol δ catalytic subunit, whereas the loci encoding the accessory subunits POLD2 and POLD3 are amplified in a very high proportion of human tumors. Consistently, DNA Pol δ is key for the survival of replication stress and is involved in multiple long-patch repair pathways. Synthetic lethality arises from compromising the function and availability of the noncatalytic subunits of DNA Pol δ under conditions of replication stress, opening the door to novel therapies. DNA polymerase δ is key to surviving replication stress, and is found in almost every oncogene-transformed mammalian cell line.Cancer-linked point mutations are found in POLD1, whereas POLD2 and POLD3 are found amplified in the vast majority of cancers.Hydroxyurea destabilizes Fe-S centers, which also compromises the stability of the DNA polymerase δ complex.Inhibitors of checkpoint kinases and reagents that compromise DNA polymerase δ activity may act synergistically to arrest growth in transformed cells.