G-Quadruplex Matters in Tissue-Specific Tumorigenesis by BRCA1 Deficiency.

Sanghyun Kim,Sohyun Hwang

doi:10.3390/genes13030391

Abstract

How and why distinct genetic alterations, such as BRCA1 mutation, promote tumorigenesis in certain tissues, but not others, remain an important issue in cancer research. The underlying mechanisms may reveal tissue-specific therapeutic vulnerabilities. Although the roles of BRCA1, such as DNA damage repair and stalled fork stabilization, obviously contribute to tumor suppression, these ubiquitously important functions cannot explain tissue-specific tumorigenesis by BRCA1 mutations. Recent advances in our understanding of the cancer genome and fundamental cellular processes on DNA, such as transcription and DNA replication, have provided new insights regarding BRCA1-associated tumorigenesis, suggesting that G-quadruplex (G4) plays a critical role. In this review, we summarize the importance of G4 structures in mutagenesis of the cancer genome and cell type-specific gene regulation, and discuss a recently revealed molecular mechanism of G4/base excision repair (BER)-mediated transcriptional activation. The latter adequately explains the correlation between the accumulation of unresolved transcriptional regulatory G4s and multi-level genomic alterations observed in BRCA1-associated tumors. In summary, tissue-specific tumorigenesis by BRCA1 deficiency can be explained by cell type-specific levels of transcriptional regulatory G4s and the role of BRCA1 in resolving it. This mechanism would provide an integrated understanding of the initiation and development of BRCA1-associated tumors.

Highlights

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The explanation given for tissue-specific tumorigenesis by breast cancer type 1 susceptibility protein (BRCA1) deficiency far is that repetitive exposure to estrogen causes a greater need for homologous recombination-based double-strand break (HR-Double strand break (DSB)) repair [18], or that BRCA1 loss of function can only be tolerated in these tissues via estrogen-induced pathway response [19]
When certain transcriptional regulations that produces many G4s are activated in specific cells, the role of BRCA1 to resolve G4s becomes important

Summary

Tissue-Specific Tumor Susceptibility of BRCA1

Mutations in BRCA1, which encodes breast cancer type 1 susceptibility protein (BRCA1) [1,2], significantly increase the cancer incidence in several tissues. BRCA1-mutant tumors are mostly high-grade serous carcinoma (HGSC) [5,6] Despite differences between these tissues, these two best-known BRCA1-deficient tumors share many molecular properties [7,8] including mutations in the tumor suppressor gene TP53, the amplification of the MYC oncogene, extreme levels of genomic instability and copy number variation (CNV), and sensitivity to DNA damage agents. We review recent studies on the importance of G4s in the mutational landscapes of the cancer genome and in cell-type-specific transcriptional regulation, and summarize the evidence that the accumulation of unresolved G4s is responsible for tissue-specific tumorigenesis by BRCA1 deficiency. General reviews of G4 can be found in recent articles [45,46,47]

G4s as the Determinants of Mutagenesis

G4s Are Key Genomic Structural Elements in Transcriptional Regulation

Findings

Discussion