# Mitotic BLM functions are required to maintain genomic stability

## TL;DR

The BLM protein plays a crucial role in resolving DNA bridges during cell division, which is essential for maintaining genomic stability.

## Contribution

A novel cell model system was developed to track BLM and UFB dynamics during mitosis using fluorescent tagging and auxin-inducible degradation.

## Key findings

- BLM localizes to UFBs and CENP-B-positive foci during anaphase, but not in interphase.
- Acute BLM depletion during mitosis leads to unresolved UFBs, micronuclei, and genomic abnormalities.
- BLM is essential for resolving ultrafine DNA bridges and preserving genomic stability during cell division.

## Abstract

The BLM helicase is a critical genome maintenance protein involved in diverse cellular processes including DNA replication, repair, transcription, and chromosome segregation. During mitosis, it cooperates with the PICH helicase and topoisomerases to resolve ultrafine DNA bridges (UFBs)—nonchromatinized DNA structures that link sister chromatids—through a mechanism that is not yet fully understood. Here, we tagged endogenous BLM and PICH with fluorescent proteins and BLM with an auxin-inducible degron to generate a cell model system that enables temporal tracking of UFB dynamics in the presence or absence of BLM. Time-resolved lattice light sheet microscopy established the dynamic localization patterns of BLM and PICH throughout the cell cycle. While BLM cycles between PML bodies and DNA repair foci in interphase, these structures disappear at the mitotic entry, and BLM then re-associates with chromatin during anaphase to UFBs as well as to CENP-B-positive mitotic foci. Acute BLM depletion during mitosis increased the fraction of unresolved UFBs, micronuclei containing acentric fragments, binucleation, and resulted in subtle genomic abnormalities detected by single-cell whole genome sequencing. These findings highlight a mitosis-specific role for BLM in UFB resolution and underscore its function in preserving genomic stability.

Graphical Abstract