Abstract
Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed.
Highlights
BRCA1-associated RING domain 1 (BARD1) was discovered in 1996 by Baer’s group who sought out to identify proteins that interacted with the N-terminus of Breast Cancer 1 (BRCA1) through a two-hybrid screening [1]
Since the BARD1 isoforms are highly expressed in non-small cell lung cancer (NSCLC), Pilyguin et al proposed that the detection of antibodies in patients’ sera against the tumor-associated antigens present on the BARD1 isoforms could be used to predict the presence of lung cancer [124]
The expression of BARD1-FL can have acquired oncogenic function in tumors where the upregulation of the DNA damage response (DDR) genes contributes to resistance to DNA damaging agents [108,109]
Summary
BARD1 was discovered in 1996 by Baer’s group who sought out to identify proteins that interacted with the N-terminus of BRCA1 through a two-hybrid screening [1]. The non-traditional orientation of the fourth ANK may be attributed to a span of 20 amino acids (a.a. 547–567), which include and extend beyond the C-terminal ANK repeat domain This region, which has no secondary structure, is called the ANK-BRCT linker region. It is thought that the different isoforms may play a role in tumorigenesis through the disrupting of BARD1’s important protein-protein interactions These variations have been well-studied in hereditary breast and ovarian cancers, the presence and functional consequences of these alterations in other cancer types are still being investigated. BARD1 and BRCA1 interact via the RING domains located at their respective N-termini This interaction allows for the formation of a heterodimer with E3 ubiquitin ligase activity [20,21]. BARD1-BRCA1 E3 ubiquitin ligase activity has been implicated in nucleosome and chromatin modulation for DNA repair as well as for signal transduction of estrogen and progesterone [25,34,35,36,37,38]
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