When PIP2 Meets p53: Nuclear Phosphoinositide Signaling in the DNA Damage Response

Abstract

The mechanisms that maintain genome stability are critical for preventing tumor progression. In the past decades, many strategies were developed for cancer treatment to disrupt the DNA repair machinery or alter repair pathway selection. Evidence indicates that alterations in nuclear phosphoinositide lipids occur rapidly in response to genotoxic stresses. This implies that nuclear phosphoinositides are an upstream element involved in DNA damage signaling. Phosphoinositides constitute a new signaling interface for DNA repair pathway selection and hence a new opportunity for developing cancer treatment strategies. However, our understanding of the underlying mechanisms by which nuclear phosphoinositides regulate DNA damage repair, and particularly the dynamics of those processes, is rather limited. This is partly because there are a limited number of techniques that can monitor changes in the location and/or abundance of nuclear phosphoinositide lipids in real time and in live cells. This review summarizes our current knowledge regarding the roles of nuclear phosphoinositides in DNA damage response with an emphasis on the dynamics of these processes. Based upon recent findings, there is a novel model for p53’s role with nuclear phosphoinositides in DNA damage response that provides new targets for synthetic lethality of tumors.

Lamin A/C and PI(4,5)P2—A Novel Complex in the Cell Nucleus

“…HGPS cells show increased apoptosis, impaired DNA damage repair, and cell cycle regulation defects, among other regulation deficiencies [ 58 ]. On the other hand, nuclear phosphoinositides, including PI(4,5)P2, have been described to be implicated in the signaling cascade that leads to the regulation of DNA repair in the nucleus [ 59 , 60 , 61 ]. Therefore, we would like to assess whether PI(4,5)P2 also interacts with progerin.…”

“…Another possible functional role of the lamin A/C—NM1—PI(4,5)P2 complex might be involvement in DNA damage response processes. Both PI(4,5)P2 [ 59 , 60 , 61 , 85 ] and NM1 [ 86 ] have been associated with DNA damage response. Hutchinson–Gilford Progeria syndrome (HGPS), which is characterized mostly by its accelerated normal human aging conditions [ 87 , 88 ], is caused by de novo mutations in the LMNA gene that activate an alternative pre-mRNA splice site leading to the expression of progerin—a lamin A mutant lacking 50 amino acids in its globular tail domain.…”

Lipid transfer proteins and a PI 4-kinase initiate nuclear phosphoinositide signaling

“…Here we reveal an unexpected role for class I PITPα/β in generating the nuclear PIPn pools that initiate nuclear PIPn signaling. Although the existence of nuclear PIPns and their role in the cell cycle 36 , oxidative stress 21,[37][38][39][40][41][42] and the DNA damage response 15,[43][44][45] is supported by emerging evidence 21 , the molecular origin and regulation of nuclear PIPns in regions devoid of membranes have been enigmatic 46 . PITPs have a well-established role in transporting PI from the endoplasmic reticulum to membranes to enable membrane-localized PIPn signaling via PIP kinases, phosphatases and phospholipase-C 23-26, 29, 47 .…”

Viruses and phospholipids: Friends and foes during infection

“…The presence of ATR and its interactor, ATR‐interacting protein (ATRIP), was suppressed by more than 80%. This indicated that nuclear phosphoinositide sequestration directly affected protein–protein interactions in the DNA damage repair network 105,106 …”

“…This indicated that nuclear phosphoinositide sequestration directly affected protein-protein interactions in the DNA damage repair network. 105,106 For the productive life cycle of alphaHPV the activation of DNA damage repair pathways is necessary. 107 However, repair pathways are inhibited by betaHPV, which in turn contributes to the persistence of UV light-induced DNA damage, and thus to the development of skin cancer.…”