PrimPol: A Breakthrough Among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Feb 25

PMID 35204749

Authors

Alberto Diaz-Talavera

Cristina Montero-Conde

Luis Javier Leandro-Garcia

Mercedes Robledo

Affiliations

Soon will be listed here.

Abstract

DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out this task. PrimPol is a primase that operates in both the nucleus and mitochondria. In contrast with conventional primases, PrimPol is a DNA primase able to initiate DNA synthesis de novo using deoxynucleotides, discriminating against ribonucleotides. In vitro, PrimPol can act as a DNA primase, elongating primers that PrimPol itself sythesizes, or as translesion synthesis (TLS) DNA polymerase, elongating pre-existing primers across lesions. However, the lack of evidence for PrimPol polymerase activity in vivo suggests that PrimPol only acts as a DNA primase. Here, we provide a comprehensive review of human PrimPol covering its biochemical properties and structure, in vivo function and regulation, and the processes that take place to fill the gap-containing lesion that PrimPol leaves behind. Finally, we explore the available data on human PrimPol expression in different tissues in physiological conditions and its role in cancer.

Citing Articles

Decoding mitochondrial DNA damage and repair associated with infection.

Shahi A, Kidane D Front Cell Infect Microbiol. 2025; 14:1529441.

PMID: 39906209 PMC: 11790445. DOI: 10.3389/fcimb.2024.1529441.

Canonical and Non-Canonical Roles of Human DNA Polymerase η.

Bedaiwi S, Usmani A, Carty M Genes (Basel). 2024; 15(10).

PMID: 39457395 PMC: 11507097. DOI: 10.3390/genes15101271.

Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse.

Mann J, Niedermayer K, Krautstrunk J, Abbey L, Wiesmuller L, Piekorz R Int J Cancer. 2024; 156(2):389-402.

PMID: 39239809 PMC: 11578078. DOI: 10.1002/ijc.35164.

Transcription-Replication Conflicts as a Source of Genome Instability.

Goehring L, Huang T, Smith D Annu Rev Genet. 2023; 57:157-179.

PMID: 37552891 PMC: 10760935. DOI: 10.1146/annurev-genet-080320-031523.

Correction: Díaz-Talavera et al. PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy. 2022, , 248.

Diaz-Talavera A, Montero-Conde C, Leandro-Garcia L, Robledo M Biomolecules. 2022; 12(5).

PMID: 35625665 PMC: 9138727. DOI: 10.3390/biom12050693.

References

Sinha N, Morris C, Alberts B . Efficient in vitro replication of double-stranded DNA templates by a purified T4 bacteriophage replication system. J Biol Chem. 1980; 255(9):4290-3. View

Pitcher R, Brissett N, Picher A, Andrade P, Juarez R, Thompson D . Structure and function of a mycobacterial NHEJ DNA repair polymerase. J Mol Biol. 2006; 366(2):391-405. DOI: 10.1016/j.jmb.2006.10.046. View

McDonald J, Frank E, Plosky B, Rogozin I, Masutani C, Hanaoka F . 129-derived strains of mice are deficient in DNA polymerase iota and have normal immunoglobulin hypermutation. J Exp Med. 2003; 198(4):635-43. PMC: 2194173. DOI: 10.1084/jem.20030767. View

Lipps G, Weinzierl A, von Scheven G, Buchen C, Cramer P . Structure of a bifunctional DNA primase-polymerase. Nat Struct Mol Biol. 2004; 11(2):157-62. DOI: 10.1038/nsmb723. View

Taglialatela A, Leuzzi G, Sannino V, Cuella-Martin R, Huang J, Wu-Baer F . REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps. Mol Cell. 2021; 81(19):4008-4025.e7. PMC: 8500949. DOI: 10.1016/j.molcel.2021.08.016. View

Salas M . Protein-priming of DNA replication. Annu Rev Biochem. 1991; 60:39-71. DOI: 10.1146/annurev.bi.60.070191.000351. View

Boldinova E, Stojkovic G, Khairullin R, Wanrooij S, Makarova A . Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol. PLoS One. 2017; 12(9):e0184489. PMC: 5597260. DOI: 10.1371/journal.pone.0184489. View

Pelletier H, Sawaya M, Kumar A, Wilson S, KRAUT J . Structures of ternary complexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP. Science. 1994; 264(5167):1891-903. View

Mislak A, Anderson K . Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol. Antimicrob Agents Chemother. 2015; 60(1):561-9. PMC: 4704227. DOI: 10.1128/AAC.02270-15. View

10.

Sheaff R, Kuchta R . Mechanism of calf thymus DNA primase: slow initiation, rapid polymerization, and intelligent termination. Biochemistry. 1993; 32(12):3027-37. DOI: 10.1021/bi00063a014. View

11.

Pavlov Y, Frahm C, Nick McElhinny S, Niimi A, Suzuki M, Kunkel T . Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta. Curr Biol. 2006; 16(2):202-7. DOI: 10.1016/j.cub.2005.12.002. View

12.

Tate J, Bamford S, Jubb H, Sondka Z, Beare D, Bindal N . COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2018; 47(D1):D941-D947. PMC: 6323903. DOI: 10.1093/nar/gky1015. View

13.

Rechkoblit O, Johnson R, Gupta Y, Prakash L, Prakash S, Aggarwal A . Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase. Nat Commun. 2021; 12(1):4020. PMC: 8241999. DOI: 10.1038/s41467-021-24317-z. View

14.

Skerra A . Phosphorothioate primers improve the amplification of DNA sequences by DNA polymerases with proofreading activity. Nucleic Acids Res. 1992; 20(14):3551-4. PMC: 334000. DOI: 10.1093/nar/20.14.3551. View

15.

Carvalho G, Diaz-Talavera A, Calvo P, Blanco L, Martinez-Jimenez M . Human PrimPol Discrimination against Dideoxynucleotides during Primer Synthesis. Genes (Basel). 2021; 12(10). PMC: 8535229. DOI: 10.3390/genes12101487. View

16.

Lujan S, Williams J, Kunkel T . DNA Polymerases Divide the Labor of Genome Replication. Trends Cell Biol. 2016; 26(9):640-654. PMC: 4993630. DOI: 10.1016/j.tcb.2016.04.012. View

17.

Grossman R, Heath A, Ferretti V, Varmus H, Lowy D, Kibbe W . Toward a Shared Vision for Cancer Genomic Data. N Engl J Med. 2016; 375(12):1109-12. PMC: 6309165. DOI: 10.1056/NEJMp1607591. View

18.

Clausen A, Zhang S, Burgers P, Lee M, Kunkel T . Ribonucleotide incorporation, proofreading and bypass by human DNA polymerase δ. DNA Repair (Amst). 2012; 12(2):121-7. PMC: 3552135. DOI: 10.1016/j.dnarep.2012.11.006. View

19.

Li H, Cuevas I, Zhang M, Lu C, Alam M, Fu Y . Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. J Clin Invest. 2018; 128(9):4179-4191. PMC: 6118636. DOI: 10.1172/JCI122095. View

20.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View