Dynamics of replication proteins during lagging strand synthesis: A crossroads for genomic instability and cancer

• Lagging strand DNA synthesis is a highly dynamic process and mainly involves RFC, PCNA, Pol δ, FEN1 and DNA Ligase I proteins.
• Protein-protein interactions and post-translational modifications necessary for successful completion of the process have been explained and summarized.
• Mutations and interaction defects in these DNA repair/replication proteins that may lead to genomic instability and cancer progression have been mentioned.
• Recent advances in targeting of DNA repair/replication proteins for cancer therapy have been explained.

DNA replication is a complex phenomenon that requires the concerted action of several enzymes, together with their protein and non-protein cofactors. In the nucleus, the two DNA strands are duplicated by two completely independent methods due to their anti-parallel orientation and the restrictive nature of DNA polymerases that allow DNA synthesis in the 5'–3' direction only. In this review, we focus on the proteins that are involved in the more complex and discontinuous process of lagging strand DNA synthesis by the formation of small DNA fragments called Okazaki fragments which are later sealed to form a continuous strand of DNA. We try and connect all the protein-protein interactions important for lagging strand synthesis in the S-phase of the cell cycle, describe the dynamics of these interactions and go on to discuss the post-translational modifications that affect them. We also look at how mutations in any of the players of the lagging strand synthesis can cause genomic instability leading to cancer and discuss if any of the players may be targeted for cancer therapy.