BRCA1 and Oxidative Stress.

Yong Yi,Insoo Bae,Hyo Kang

doi:10.3390/cancers6020771

Abstract

The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.

Highlights

Mutations of breast cancer susceptibility gene 1 (BRCA1) are found in a high percentage of hereditary breast and ovarian cancers [1]
In this background MNAN-treated mice had a significantly increased esophagus and forestomach tumor incidence as compared with that of control mice. The significance of these MNAN-induced tumors is not yet understood in human BRCA1-related cancers, these results suggest that Brca1 is involved in the regulation of reactive oxygen species (ROS) in carcinogenesis of the mouse
Rad3-related (ATR) proteins in response to gamma- and UV-irradiation, respectively [90]. These results suggest that BRCA1 potentially contributes to the oxidative stress response through the regulation of p53, further experiments are needed to determine the exact role of BRCA1/p53 in this regulation

Summary

Introduction

Mutations of BRCA1 are found in a high percentage of hereditary breast and ovarian cancers [1]. The BRCA1 gene is conserved in mammals [21,22] and the BRCA1 protein has roles in various cellular events including cell cycle control, DNA damage signaling, maintaining genomic integrity, protein ubiquitination, and transcriptional regulation. All these responsibilities of BRCA1 may collectively participate in tumor suppression; precise mechanisms of how the BRCA1 protein functions as a tumor suppressor are still not yet fully understood [23,24]. Given that the mechanisms of BRCA1 tumor suppression have not yet been fully elucidated, we summarize and explore the potential role of BRCA1 in response to ROS and carcinogenesis in the context of its known functions

BRCA1 as a Tumor Suppressor

Mouse Model

Cell Studies

BRCA1 and p53

BRCA1 as an E3 Ubiquitin Ligase

BRCA1 E3 Ligase Activity and Tumor Suppression

BRCA1: Oxidative Stress and Ubiquitination

BRCA1 as a Transcriptional Regulator

Binding Partners in BRCA1 Transcriptional Regulation

BRCA1 Regulation of Oxidative Stress through Transcriptional Activities

Conclusions

Conflicts of Interest