POLDIP3: At the Crossroad of RNA and DNA Metabolism

Abstract

POLDIP3 was initially identified as a DNA polymerase delta (Pol δ) interacting protein almost twenty years ago. Intriguingly, it also interacts with proteins involved in a variety of RNA related biological processes, such as transcription, pre-mRNA splicing, mRNA export, and translation. Studies in recent years revealed that POLDIP3 also plays critical roles in disassembling genome wide R-loop formation and activating the DNA damage checkpoint in vivo. Here, we review the functions of POLDIP3 in various RNA and DNA related cellular processes. We then propose a unified model to illustrate how POLDIP3 plays such a versatile role at the crossroad of the RNA and DNA metabolism.

TDP-43 Epigenetic Facets and Their Neurodegenerative Implications

“…Despite the demonstration being conducted in cycling cells, SIRT1 implication in the NHEJ DDR pathways could also be effective in cells post-mitotically, and it could be linked to its protective roles in several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and ALS [ 104 ]. On the other hand, POLDIP3 plays critical roles in disassembling R-loops genome-wide and activating the DNA damage checkpoint [ 105 ], and its transcript is one of the well-characterized TDP-43 targets. In particular, inclusion of POLDIP3 exon 3 was significantly altered in different cell lines depleted for TDP-43 and other hnRNPs linked to TDP-43 functions [ 59 , 77 , 78 ], as well as in various motor regions of CNS of ALS patients [ 106 ].…”

Special Issue “DNA Replication/Repair, and the DNA Damage Response in Human Disease”

“…Subsequently, the Lee lab demonstrated that POLDIP3 has a critical role in regulating the enzymatic activity of DNA polymerase δ [ 4 ]. In a review article, Singh and colleagues discuss the biochemical and biological functions of POLDIP3, not only in the context of DNA metabolism, but also its role in various RNA metabolic pathways [ 12 ]. In partnering with DNA polymerase δ, the flap endonuclease 1 (FEN1) has a significant function in Okazaki fragment maturation [ 5 ] and in processing DNA–RNA hybrids, i.e., R-loops [ 13 ].…”

“…In a review article, Barnes and colleagues discussed the molecular mechanism of MiDAS in the context of telomeres [ 19 ]. Additionally, since both POLDIP3 and BIR have been implicated in the ALT pathway, the two articles written by Singh et al and Riders et al are valuable resources to further the understanding of the ALT pathway [ 10 , 12 ]. Finally, Batista and colleagues summarized the biology and therapeutics of Hutchinson-Gilford Progeria Syndrome (HGPS), one of the premature aging syndromes [ 20 ].…”