BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

Ielizaveta Gorodetska, Iryna Kozeretska, Anna Dubrovska, Ielizaveta Gorodetska, Iryna Kozeretska, Anna Dubrovska

Abstract

Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.

Keywords: BRCA1; BRCA2; cancer stem cells; cancer treatment; genomic instability.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Schematic representation of functional domains within BRCA1 and BRCA2 proteins and the position of several founder mutations. BRCA1 is composed of 23 exons and BRCA2 includes 27 exons. Both genes encode large proteins: BRCA1 consists of 1,863 amino acids and BRCA2 of 3,418 amino acids. BRCA1 has a highly conserved zinc-binding RING (really interesting new gene) finger domain which is located close to the N-terminus. At the C-terminus, two BRCT (BRCA1 C-terminal) domains are located. The central part of BRCA1 consists of two NLS (nuclear localization signals) and one coiled coil domain. BRCA2 contains eight copies of a 20-30 amino acid repeat, termed BRC repeats. At the amino-terminus, BRCA2 has a TAD (transcriptional activation domain) domain and at the carboxyl-terminus two NLS and one TR2 domain. DNA-binding domain is located close to the C-terminal region and is composed of a conserved helical domain (H), three oligonucleotide binding (OB) folds and a tower domain (T). Domains are indicated by violet (BRCA1) and green (BRCA2) boxes. Domain names are shown above. Exons are indicated by braces. Positions of founder mutations are indicated beneath.
Figure 2
Figure 2
Functional features of BRCA proteins. The BRCA1 protein has multiple functions in different cellular processes, including DNA repair, transcriptional activation, cell cycle regulation and chromatin remodeling. BRCA2 plays a role in transcriptional and cell cycle regulation, DNA repair, mitophagy and stabilization of replication fork. BRCA proteins and interacting partners are shown. Functions of proteins are shown in rectangles. Interacting partners are shown in blue ovals.
Figure 3
Figure 3
CSC signaling pathways which are regulated by BRCA proteins. BRCA1 directly binds to JAK1 and JAK2 and leads to constitutive activation of STAT3 , , . BRCA1 modulates genes involved in the Hedgehog pathway such as SHH, IHH, DHH, Gli1 and PATCH1 . BRCA1 transcriptionally upregulates the Notch ligand JAG1 (Jagged1) with further activation of the Notch pathway , . The loss of BRCA1 constitutively activates PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase)/AKT (Protein kinase B) pathway through down-regulation of phospho-AKT .

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