# β‐TrCP overexpression enhances cisplatin sensitivity by depleting BRCA1

## TL;DR

This study shows that increasing β-TrCP levels makes cancer cells more sensitive to cisplatin by reducing BRCA1, a protein that helps repair DNA damage.

## Contribution

The study reveals that β-TrCP enhances cisplatin sensitivity by degrading BRCA1 through lysosomal and proteasomal pathways.

## Key findings

- Overexpression of β-TrCP increases DNA damage and cisplatin-induced apoptosis in tumor cells.
- BRCA1 and CtIP interact with β-TrCP and their levels are regulated by β-TrCP expression.
- β-TrCP-mediated BRCA1 degradation impairs homologous recombination repair, leading to cisplatin sensitivity.

## Abstract

Cisplatin is one of the most used anticancer chemotherapy agents; however, over time, patients develop resistance to the treatment, and survival rates drop dramatically. Investigation of tumor cell resistance mechanisms could increase sensitivity and prevent cancer progression. Here, we investigated the role of the E3 ubiquitin ligase SCF (β‐TrCP) in cisplatin resistance in different tumor cell lines, analyzing its role in the stability of BRCA1 and CtIP, proteins involved in DNA damage repair by homologous recombination. We showed that SCF(β‐TrCP) plays a key role in cisplatin response, as overexpression of wild‐type β‐TrCP increased DNA damage and cisplatin‐induced apoptosis, while overexpression of a dominant‐negative mutant or siRNA‐mediated downregulation of β‐TrCP decreased the damage and conferred treatment resistance. Furthermore, we demonstrated that BRCA1 and CtIP interacted with β‐TrCP in vivo, and their levels changed when β‐TrCP expression was modulated. We also described that β‐TrCP‐mediated BRCA1 degradation involves both lysosomal and proteasomal pathways. Mechanistically, the failure of β‐TrCP to regulate the degradation of BRCA1 enables a more efficient DNA damage repair and thereby the acquisition of cisplatin resistance. Overall, β‐TrCP overexpression sensitizes cisplatin‐induced DNA damage by depleting BRCA1.

Low levels of β‐TrCP (Panel A) allow the accumulation of BRCA1 and CtIP, which facilitate the repair of cisplatin‐induced DNA damage via homologous recombination (HR) and promote tumor cell survival. In contrast, high β‐TrCP expression (Panel B) leads to BRCA1 and CtIP degradation, impairing HR repair, resulting in persistent DNA damage and apoptosis. Therefore, β‐TrCP emerges as a key regulator of cisplatin sensitivity.