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

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.

Keywords: BRCA1; BRCAness; G-quadruplex (G4); R-loop; basal-like breast cancer; base excision repair; high-grade serous ovarian carcinoma (HGSC); oxidative genome damage; tissue-specific-tumorigenesis.

Figure 1

The structure and topologies of G4. (A) Structure of a G-quartet formed by hydrogen bonded four guanines and central cation (blue). (B) The consensus sequence of G4. Representative topologies of unimolecular G4s based on the strand direction: (C) antiparallel, (D) parallel, and (E) hybrid.

Figure 2

Proposed mechanism of G4/BER-mediated transcriptional activation. (A) Local ROS generates 8-OxoG in the G-rich regions of the promoter, (B) which is removed by OGG1 to form an AP site. (C) The AP site rearranges the DNA duplex into a G4 structure, and (D) a more stable G4 can be formed by involving the fifth G track and looping out the AP site. (E) APE1 can bind the AP site and recruit TFs.

Figure 3

Model for tissue-specific tumorigenesis by BRCA1 deficiency. (A) How much of transcription regulatory G4/R-loop is generated at basal level is cell-type specific. (B) High burden on G4 processing causes multi-level molecular alterations by BRCA1 haploinsufficiency in the form of: (i) transcriptional alterations, (ii) epigenetic alterations, and (iii) genetic alterations. (C) These alterations contribute to phenotype evolution and modify the biological context of the cell by various factors, such as SIRT1, NRF2, estrogen receptor (ER)-E2 signaling, and RANK-RANKL signaling. Clones with the same pattern of copy number variations (CNVs) or single nucleotide variations (SNVs) expand as the tumor grows. One of the clonal expansion models for CNV, the Crisis and stasis model [178], is shown.