The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks.

Máté A Demény,László Virág

doi:10.3390/cancers13092042

Abstract

Simple SummaryPoly (ADP-ribose) polymerase (PARP) proteins regulate DNA damage correction, replication, and gene transcription. By controlling pivotal aspects of these processes, PARPs are heavily implicated in cancer development. Inhibitors of PARPs, approved for cancer chemotherapy a few years ago, have achieved great success against tumors of the breast and ovary carrying mutations in the BRCA1/2 genes. The spectrum of the inhibitors is avidly sought to be extended to tumors with different genetic backgrounds and cancers of other origins. This pursuit requires thorough apprehension of PARP-dependent processes affecting cancer development. The hallmarks of cancer are acquired by defining capabilities that differentiate cancer cells from their normal counterparts. Here, in two joint papers, we walk through the connections between these cancer traits and PARP functions. The present review focuses on how PARPs affect the features of cancer that can be attributed to cell-intrinsic changes increasing proliferative potential and survival capabilities. In a kindred paper, we explore the PARP association of cancer hallmarks that derive from tissue-level reorganization in tumors and intercellular interactions of cancer cells.The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

Highlights

The PARP enzyme family, consisting of members (the original publication reported PARP superfamily members but later tankyrase 3 turned out to be a shorter splice variant of tankyrase 2 (TNKS2)), was first described in 2004 as a group of proteins sharing the conserved PARP signature sequence [1] (Supplementary Figure S1)
The roles of PARP enzymes in various hallmarks of cancer (HoC) as discussed in this paper and in the companion paper must be viewed in their complexities [18]
PARP inhibitors (PARPi) were initially developed with the goal of suppressing DNA damage repair and achieving a high level of replication stress that would eventually engage the same cell death pathways that are activated in response to DNA damage-inducing cytotoxic chemotherapies [242]

Summary

Introduction

The PARP enzyme family, consisting of members (the original publication reported PARP superfamily members but later tankyrase 3 turned out to be a shorter splice variant of tankyrase 2 (TNKS2)), was first described in 2004 as a group of proteins sharing the conserved PARP signature sequence [1] (Supplementary Figure S1). ADP-ribosylation plays a role in DNA repair, replication, transcription, telomere dynamics, and metabolism [5] Through these molecular events, ADP-ribosylation regulates cell proliferation, differentiation, cell death, and immunity, implicating PARPs in cancer development [9]. Senescence is a special form of cell cycle arrest representing an escape mechanism for cancer cells [47] Both p53 and pRb are mediators of the senescence process, which leads cells to a viable, actively metabolic but nonproliferative state [47]. This process is accompanied by downregulation of PARP1 expression via transcription factors, factors 1 and 3 (Sp1 and Sp3), as demonstrated in various primary cells [53] and in keratinocytes [54] This may be related to intrinsic cell cycle-related gene regulation [55,56] and/or integrin signaling [57]. How PARP1 expression changes when neoplastic cells are in contact with each other (e.g., in 2D or 3D cell culture models or in vivo tumors) and how adhesion factors in the tumor stroma affect PARP1 expression are largely unexplored

Resisting Cell Death

Enabling Replicative Immortality

Genome Instability and Mutation

Reprogramming Energy Metabolism

Conclusions