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Last update 08 May 2025

PELO

Last update 08 May 2025

Basic Info

Synonyms

PELO, pelota mRNA surveillance and ribosome rescue factor, Protein pelota homolog

Introduction

Component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway (PubMed:21448132, PubMed:23667253, PubMed:27543824, PubMed:27863242). In the Pelota-HBS1L complex, PELO recognizes ribosomes stalled at the 3' end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel (PubMed:27543824, PubMed:27863242). Following mRNA extraction from stalled ribosomes by the SKI complex, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway (PubMed:21448132, PubMed:32006463). As part of the PINK1-regulated signaling, upon mitochondrial damage is recruited to the ribosome/mRNA-ribonucleoprotein complex associated to mitochondrial outer membrane thereby enabling the recruitment of autophagy receptors and induction of mitophagy (PubMed:29861391).

Drugs associated with PELO

HBS1L/PELO Complex(Tango)

Target

EF-1A x PELO

Mechanism

EF-1A modulators [+1]

Active Org.

Tango Therapeutics, Inc.

Originator Org.

Tango Therapeutics, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PELO

100 Translational Medicine associated with PELO

0 Patents (Medical) associated with PELO

Literatures (Medical) associated with PELO

01 Apr 2025·Clinical and Translational Science

Genome Wide Association Study (GWAS) Identifies Novel Genetic Loci for Second‐Generation Antipsychotics (SGA)‐Induced Metabolic Syndrome (MetS)

Article

Author: Owusu‐Obeng, Aniwaa ; DelBello, Melissa ; El Rouby, Nihal ; Preuss, Michael H. ; Mosley, Jonathan D. ; Van Driest, Sara L. ; Shi, Mingjian ; Lee, Simon ; Nadukuru, Rajiv

ABSTRACTSecond‐generation antipsychotics (SGA) are widely used for treating psychiatric disorders; however, their use is associated with an increased risk of metabolic syndrome (MetS). To identify common genetic associations of SGA‐induced metabolic syndrome (SGA‐MetS), we conducted a genome‐wide association study (GWAS) in a diverse patient population within the BioVU and BioMe electronic health records (EHRs)‐linked biobanks. Additionally, we performed Mendelian Randomization (MR) analysis to investigate the association between the individual metabolic parameters comprising MetS (body mass index [BMI], fasting glucose, blood pressure, HDL, and triglycerides) and SGA‐MetS. The meta‐analysis of European ancestry GWAS from BioVU and BioMe (N = 9248) identified a genome‐wide signal (rs61900075, β = −0.27, SE = 0.05, p = 1.6 × 10−8) on chromosome 11. Multiple associated variants met the suggestive level of association (p ≤ 10−5) in the PELO‐ITGA1 locus on chromosome 5 and were associated among the Hispanic Ancestry within BioMe. The meta‐analysis of the African Ancestry patients of BioVU and BioMe (N = 2018) identified multiple genome‐wide signals that were functionally mapped to NPPC‐DIS3L2 in chromosome 2. Finally, the inverse‐variance weighted average MR (BMI: OR = 1.2, 95% CI: 1.1–1.4, p = 0.002) showed that genetically predicted, higher BMI was associated with an increased risk of SGA‐MetS. Similar results were seen in the sensitivity analyses using the weighted median and Egger MR. This study identified novel variants for SGA‐MetS and suggested a role of BMI in increasing the risk of SGA‐MetS. The findings highlight the value of EHR biobanks for identifying the genetics underlying SGA‐MetS. The associations in chromosome 2 and 5 will need further replication.

27 Feb 2025·Nature

SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO

Article

Author: Li, Tianxia ; Aquilanti, Elisa ; Das Sharma, Sohani ; Chan, Tessla ; Prensner, John R ; Lubicki, Daniel A ; Foster, Kyla ; Lofaso, Nicholas J ; Borah, Ashir A ; Lau, Anthony C ; Boyle, Isabella ; Golub, Todd R ; Chan, Edmond M ; Dempster, Joshua M ; Kishen, Riya V ; Vazquez, Francisca ; Jankovic, Kristina ; Campbell, Catarina D ; Bick, Nolan ; Borck, Patricia C ; Krill-Burger, J Michael ; Raghavan, Srivatsan ; Parker-Burns, Lucy I ; Adeagbo, Anisah

AbstractCancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach1–3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO, for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.

27 Feb 2025·Nature

Synthetic lethality of mRNA quality control complexes in cancer

Article

Author: Widomski, Deborah ; Chen, Anlu ; Sher, Kimberly R ; Sandoval, Stephanie ; Prindle, Vivian ; Kongpachith, Sarah ; Dezso, Zoltan ; Meulbroek, Jonathan A ; Pappano, William N ; Palczewski, Marianne B ; Verduzco, Daniel ; Richardson, Adam E ; Walker, Stephen ; Shi, Xu ; Cheng, Dong ; Manaves, Vlasios ; Lu, Charles ; Plotnik, Joshua P ; Mitra, Diya ; Torrent, Maricel ; Kentala, Kaitlin ; Le, Phuong ; Petiwala, Sakina ; Bierie, Brian ; Buchanan, F Gregory

Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer¹. Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors² and ushered several next-generation therapeutic targets such as WRN³, USP1⁴, PKMYT1⁵, POLQ⁶ and PRMT5⁷ into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO-HBS1L and SKI complexes of the mRNA quality control pathway. In distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumours, we found that phenotypically destabilized SKI complex leads to dependence on the PELO-HBS1L ribosomal rescue complex. PELO-HBS1L and SKI complex synthetic lethality alters the normal cell cycle and drives the unfolded protein response through the activation of IRE1, as well as robust tumour growth inhibition. Our results indicate that PELO and HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts representing a significant population of patients with cancer.

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