# REV1 Loss Triggers a G2/M Cell-Cycle Arrest Through Dysregulation of Mitotic Regulators

## TL;DR

This study shows that losing the REV1 protein causes cells to stop dividing at a specific stage, which could help understand cancer cell behavior.

## Contribution

The study reveals a new role for REV1 in cell cycle regulation, specifically in G2/M arrest, beyond its known DNA repair functions.

## Key findings

- REV1 loss causes G2/M cell cycle arrest in flow cytometry analysis.
- REV1-deficient cells show dysregulation of G2/M regulators like Cyclin B1 and tubulins.
- Phosphorylation of histone H3 is reduced in REV1-deficient cells.

## Abstract

Background: Genomic integrity is crucial to the cellular life cycle, which involves a tightly regulated process where cells progress through specific phases to ensure that fully replicated, undamaged DNA is inherited by daughter cells. Any dysfunction in this process or unrepaired DNA damage leads to cell cycle arrest and programmed cell death. Cancer cells are known to exploit these mechanisms to continue dividing. Usually, DNA damage arrests replication, allowing the DNA Damage Response (DDR) pathway to activate, which repairs the DNA or bypasses the damage to support cell survival and preserve genome integrity. For DNA damage bypass or translesion synthesis (TLS), a group of low-fidelity polymerases perform error-prone DNA synthesis opposite damaged bases, where REV1 functions as the main scaffolding protein. Previously, we reported non-TLS functions of REV1, including its role in triggering DNA damage-dependent specific DNA metabolic processes. Methods and Results: In this study, we demonstrate that REV1 plays a significant role in cell cycle progression and that its loss causes arrest at the G2/M phase in flow cytometry analysis. This unexpected phenotype includes dysregulation of G2/M regulators, such as Cyclin B1 and tubulins, in REV1-deficient cells compared to controls, as quantified by Western blot. Additionally, phosphorylation of histone H3 at serine 28 was significantly reduced in these REV1-deficient cells. These G2/M arrest features were even more pronounced in REV1-deficient cells treated with the tubulin inhibitor colchicine. Conclusions: Overall, this study reveals a previously unrecognized link between REV1 TLS polymerase inhibition and the G2/M cell cycle arrest.