Barrier-to-autointegration factor protects against the cGAS-STING response to chromatin bridges

Abstract

Cellular damage or stress can lead to disorganization, mislocalization or damage to self-DNA that can activate intracellular innate immune response mechanisms. Micronuclei, such as can occur following mitotic defects, have been proposed as a source of DNA capable of activating the cGAS-STING pathway, resulting in IRF3-dependent proinflammatory transcription.

Introduction

Mitotic defects often lead to errors in chromosome segregation and genomic instability that can contribute to cancer progression [1,2]. Cancer cells often acquire structural nuclear defects [3,4]. Innate immune responses against foreign, mislocalized DNA or abnormal DNA-protein complexes can be co-opted to protect the organism against potentially hazardous cells resulting from mitotic defects [5,6]. Precisely which type of defective structures are detected and the nature of the downstream innate immune cascades being activated are incompletely understood.

Materials and method

DNA constructs

GFP-cGAS and GFP-BAF lentiviral vectors were generated by Gateway cloning. BAF and cGAS coding sequences flanked with attB sites were cloned into the entry vector pDONR221 and then recombined into pLVpuro-CMV-Nterm-eGFP expression vector for lentivirus production and stable transduction in cells (Addgene plasmid #122848).

Results

BAF depletion enhances a cGAS-STING dependent response induced by Reversine treatment We hypothesized that combining inhibition of the Spindle-Assembly Checkpoint (SAC) and BAF depletion, by enhancing post-mitotic micronucleation, would synergize in the induction of the cGAS-STING response (S1 Fig). Inhibition of the SAC using the MPS1 inhibitor Reversine results in anaphase bridges and lagging chromosomes that often become micronuclei during telophase [3,33,34]. 

Discussion

The interplay between mitosis and innate immunity to self-DNA has been the subject of many recent studies [21,48–50]. However, the precise nature of post-mitotic defects capable of triggering an innate immune response remained unclear. Studies in mice implicated micronuclei as activators of cGAS [22,23]. 

Acknowledgments

BJ-5ta WT and cGAS KO cells were generously donated by Tim Mitchison (Harvard University). MDA-MB-231 and HeLa cells expressing H2B-mCherry and α-tubulin-GFP were kindly given by Beth Weaver (U. Wisconsin-Madison) and Daniel Gerlich (IMBA, Vienna), respectively. MDA-MB-231 cells were a gift from Geneviève Deblois (IRIC-Université de Montréal). 

Citation: Chastant L, Normandin K, El-Mortada F, Servant MJ, Archambault V (2026) Barrier-to-autointegration factor protects against the cGAS-STING response to chromatin bridges. PLoS Genet 22(6): e1012191. https://doi.org/10.1371/journal.pgen.1012191

Editor: Jennifer A. Benanti, UMass Chan Medical School: University of Massachusetts Chan Medical School, UNITED STATES OF AMERICA

Received: December 18, 2025; Accepted: May 29, 2026; Published: June 3, 2026

Copyright: © 2026 Chastant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This work was supported by grants from the Canadian Institutes of Health Research (VA and MJS), the Cancer Research Society (VA), the Natural Sciences and Engineering Council of Canada (VA) and by a generous donation from the Fonds de la famille Blais (VA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.