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.

Epigenomic Features and Potential Functions of K+ and Na+ Favorable DNA G-Quadruplexes in Rice

“…It has been documented that there are canonical and non-canonical types of PQSs in eukaryotic genomes. They have structural variations strictly depending on their underlying DNA sequences, such as the length and the constituent bases of the loops, base modifications, the strand direction, and the number of G tracks [ 60 ]. To assess if there are any differences of PQS subtypes in each subtype of IP-G4s, we identified PQSs within IP-G4 peaks using the regular expression, as previously reported [ 41 ].…”

Prediction and validation of circulating G-quadruplexes as a novel biomarker in colorectal cancer

“…G4 is a unique genomic structure composed of multiple guanine nucleotides that plays a significant role in various biological processes. In recent years, emerging evidence has linked G4 formation to tumorigenesis, making it a promising target for cancer treatment ( 20 - 24 ). Our study aimed to explore the relationship between G4 formation and tumor development and to investigate the therapeutic potential of targeting G4 structures in cancer treatment ( 7 , 25 , 26 ).…”

Increased Age-Adjusted Cancer Mortality After the Third mRNA-Lipid Nanoparticle Vaccine Dose During the COVID-19 Pandemic in Japan

“…ERα-mediated transcription may induce endogenous DNA double-strand breaks (DSBs) in ER-sensitive cancers [86]. Studies have shown that transcriptionally activated ERα induces DSBs by topoisomerase II and the recently known R-loop/G-quadruplex structures formation, significantly increasing the need for BRCA1 for their repair in breast cancer cells [87][88][89]. One study showed nuclear translocation of mRNA and S protein with the nuclear localization signal [90], and an in silico bioinformatic analysis showed interactions between the S2 subunit of S-protein and BRCA1, BRCA2, and P53 [91], possibly resulting in their sequestration and dysfunction.…”