When Endoplasmic Reticulum Proteostasis Meets the DNA Damage Response

Alteration in the genome integrity has been associated with disruption of the endoplasmic reticulum (ER) proteostasis. The unfolded protein response (UPR) and the DNA damage response (DDR) play important roles in the development and progression of several diseases including cancer. The UPR sensors IRE1α, PERK, and ATF6α play a role in the response to genotoxic and ER stress in cells by interacting with DNA damage proteins (e.g., ATM, ATR, p53, p21, Chk1, and Chk2). Crosstalk between UPR and DDR may contribute to cancer progression. Indeed, CHOP and p53 play a central role in the crosstalk between UPR and DDR. The pharmacologic modulation of the UPR could enhance the effectiveness of chemotherapy and radiotherapy. Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology. Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology. a key endoplasmic reticulum (ER) chaperone and master regulator of ER functions under ER stress. The detection of misfolded proteins by the three UPR sensors is partly dependent on BiP. any factor that is independent of the genetic background or DNA alterations, such as hypoxia, glucose deprivation, and inadequate amino acid supplies. any factor that is dependent on the genetic background or DNA, such as oncogene activation, chromosome number alterations, chromosome rearrangements, and hyperploidy. a cellular response that involves DNA damage recognition, followed by the initiation of a cellular signaling cascade that promotes DNA repair and can modulate cell-cycle progression, chromatin structure, and transcription both at sites of DNA damage and globally. The DDR induced by DSBs is controlled by three related kinases: ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PKcs). different classes of DNA damage such as UV light, radiation, DNA-damaging drugs, and oxidative stress can lead to DNA rupture in both strands. If DNA is not repaired correctly, DSBs can cause deletions, translocations, and fusions of the DNA. the principal quality-control mechanism that targets misfolded ER proteins for cytosolic degradation. ERAD targets are destroyed by the cytoplasmic ubiquitin–proteasome system. Many ER chaperones participate in the ERAD complex, including BiP, EDEM1, OS9, and XTP3B. The UPR sensor IRE1α and SEL1L– HRD1 complexes are the two most conserved branches of ER quality-control mechanisms. includes all processes that maintain the integrity of DNA, such as sensing, signaling, and repair of DNA damage, processing of DNA damage in the context of chromatin and chromosomes, cell-cycle checkpoint control, and apoptosis control. Effective maintenance of GI is essential for healthy organisms, in aging, and for disease prevention. upon DSB induction, the histone variant H2AX is phosphorylated on serine 139 by ATM, ATR, or DNA-PK, generating phosphorylated H2AX, namely γH2AX. γH2AX induction is one of the earliest events detected in cells and human biopsies following exposure to DNA damaging agents. γH2AX is a key marker of DSB damage, allowing the activation and relocalization of repair proteins to DSB sites as well as signal amplification. imbalance between the production of reactive oxygen species (ROS, free radicals) and antioxidant defenses. Amino acids such as proline, arginine, lysine, and threonine are particularly vulnerable to oxidative damage, both as free molecules or within proteins. Moreover, oxidative damage can also affect the integrity and stability of DNA and RNA. a network of interconnected quality-control processes in the cell that maintain a functional proteome. Chaperones, foldases, oxidoreductases, and glycosylating enzymes ensure that secretory proteins are properly folded, modified, and assembled into multiprotein complexes in the ER before they transit further downstream in the secretory pathway. a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell. The UPR is transduced by three principal ER-resident proteins: inositol-requiring protein 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6α (ATF6α).