PXL: a nucleic acid-binding module of the promyelocytic leukemia protein
TL;DR
It is reported that PML-1 itself harbors a previously structurally uncharacterized nucleic acid-binding domain, termed PXL, which is unique to isoform 1 and specifically binds G-rich oligonucleotides implicated in G-quadruplex formation and displays a strong in vitro preference for polyUG RNA.
Abstract
Abstract The promyelocytic leukemia protein (PML) is a stress-response factor that assembles into PML nuclear bodies, dynamic subnuclear compartments involved in tumor suppression and antiviral defense. The most abundant isoform, PML-1, has been linked to transcriptional regulation, genome stability, and antiviral responses, yet the molecular basis of these functions remains unclear and is generally attributed to proteins associated with PML nuclear bodies. Here, we report that PML-1 itself harbors a previously structurally uncharacterized nucleic acid-binding domain. The domain, termed PXL, is encoded by exon 9 of the PML gene and is unique to isoform 1. Its structure reveals an exonuclease III fold, but lacks the catalytic residues required for activity, defining PXL as a pseudo-exonuclease. Biochemical, structural, mutational, and cellular analyses demonstrate that PXL specifically binds G-rich oligonucleotides implicated in G-quadruplex formation and displays a strong in vitro preference for polyUG RNA. Furthermore, deletion of the PXL domain significantly decreases PML colocalization with G-quadruplexes in cells, downregulates genomic maintenance pathways, and modulates the expression of E2F target and interferon-α response genes. These findings provide a molecular basis for previous observations implicating PML in nucleic acid-associated functions and establish a mechanistic framework for future studies of PML-mediated stress responses, nuclear organization, and gene regulation.
