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Kim, S. Consequence of BRCA1 Haploinsufficiency. Encyclopedia. Available online: https://encyclopedia.pub/entry/20831 (accessed on 08 December 2025).
Kim S. Consequence of BRCA1 Haploinsufficiency. Encyclopedia. Available at: https://encyclopedia.pub/entry/20831. Accessed December 08, 2025.
Kim, Sanghyun. "Consequence of BRCA1 Haploinsufficiency" Encyclopedia, https://encyclopedia.pub/entry/20831 (accessed December 08, 2025).
Kim, S. (2022, March 22). Consequence of BRCA1 Haploinsufficiency. In Encyclopedia. https://encyclopedia.pub/entry/20831
Kim, Sanghyun. "Consequence of BRCA1 Haploinsufficiency." Encyclopedia. Web. 22 March, 2022.
Consequence of BRCA1 Haploinsufficiency
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This entry is adapted from the peer-reviewed paper 10.3390/genes13030391

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. The consequences of BRCA1 haploinsufficiency in the context of tissue provide hints. 

BRCA1 G-quadruplex (G4) R-loop tissue-specific-tumorigenesis basal-like breast cancer

1. BRCA1 Heterozygosity Cause a Cell-Type Specific Haploinsufficiency for Resolving G4s

BRCA1 involvement in the link between DNA damage and G4 accumulation was also revealed by a study that evaluated the functional sufficiency of heterozygous BRCA1 in histologically normal mammary tissue [1]. This was performed to identify a driving factor to initiate the mammary tumorigenic process, as inherited mutations in BRCA1 are known to cause specific molecular and cellular alterations in breast tissue even before cancer development [2][3][4][5]. BRCA1 mut/+ retained normal functions of centrosome number control, spindle pole formation, and satellite RNA suppression [1]. In addition, there was no significant difference between BRCA1 +/+ and mut/+ for DNA damage checkpoints, when assessing the proportion of DNA-synthesizing cells after UV-induced DNA damage. The same result was observed for DNA repair function, assessed by RAD51 recruitment as an indicator of a key step in HR and sensitivity measurement to PARP inhibitors. However, in the presence of replicating-stalling agents such as hydroxyurea (HU) or UV radiation, BRCA1 mut/+ exhibited inefficient recruitment of phospho-RPA32 on chromatin, an abnormally high frequency of collapsed forks, and increased degradation of the nascent replicating strand. Furthermore, in the presence of sufficient replication stress, HR-DSB repair was also defective in BRCA1 mut/+ cells. This is known as “conditional haploinsufficiency” of BRCA1 mut/+ for HR-DSB repair, wherein the pool of BRCA1 available for previously intact functions is reduced [1]. The limited quantity of BRCA1 may induce innate or conditional haploinsufficiency depending on the biological context or environmental stimulus.
However, deficiency in SFR may not be simply a deficiency in SFR itself, but a consequence of defective G4 resolution. When evaluating BRCA1 functional sufficiency, an assessment for SFR was performed using the common replicating-stalling agents, HU and/or UV [1]. Although HU is mostly known to deplete nucleotide pools by inhibiting ribonucleotide reductase, which catalyzes the rate-limiting step in the biosynthesis of dNTP precursors [6], a recent report suggested that HU not only depletes nucleotides, but also induces G4 formation, followed by G4-dependent DNA damage, heterochromatin formation, and perturbed gene expression [7]. Across the genome, chronic exposure to HU results in an altered pattern of gene expression similar to that seen in cells lacking the G4-unwinding helicases FANCJ, WRN, and BLM. The affected genes were enriched in the G4 motifs [7]. In addition, when assessing the functional sufficiency of heterozygous BRCA1 [1], global G4 accumulation and alterations in gene expression observed in normal mammary epithelial cells from BRCA1-mutation carriers compared to wild-type carriers [3][5], were overlooked. Therefore, G4 resolution may be the first defective function of BRCA1 haploinsufficiency, and BRCA1 haploinsufficiency for SFR may be a conditional insufficiency after the accumulation of unresolved G4s.

2. Altered Gene Expression Caused by BRCA1 Haploinsufficiency Can Lead to Cell-Type-Specific Genomic Instability and Premature Senescence

Interestingly, rather than BRCA1 haploinsufficiency for SFR, haploinsufficiency for G4 resolution causing altered gene expression seems to result in cell-type-specific genomic instability [8]. Once G4s accumulate, haploinsufficiency for SFR is not limited to a certain cell type, as observed in both fibroblasts and epithelial cells [1]. However, G4/R-loop accumulation by BRCA1 haploinsufficiency and consequent alterations in gene expression are cell-type-specific [9]. Among genes whose expression is altered by misregulated G4s, key phenotypic regulators may be included [8]. BRCA1 haploinsufficiency leading cell type-specific genomic instability and phenotype was examined in the primary cells of disease-free breast and skin tissue from either BRCA1 mutant or wild-type carriers [8]. Prolonged passage of BRCA1 heterozygous cells showed cell type-specific phenotypes. Human mammary epithelial cells from BRCA1 mut/+ have been reported to exhibit increased genomic instability, rapid telomere erosion, and premature BRCA1 haploinsufficiency-induced senescence. Primary keratinocytes showed premature senescence, but were not associated with telomere dysfunction. Fibroblasts, either from the human mammary or dermis, did not exhibit premature senescence [8].
This cell-type-specific phenotype caused by BRCA1 haploinsufficiency was found to be related to NAD+ dependent deacetylase SIRT1 at molecular level [8]. A decrease in the SIRT1 levels leads to the accumulation of acetylated H4K16 (histone H4 on lysine 16) and acetylated pRb, thereby resulting in telomere erosion, genomic instability, and pRb-dependent premature senescence. This implies that the phenotype with premature senescence and telomere erosion in the long-term culture of BRCA1 mut/+ cells is associated with the misregulation of SIRT1 by BRCA1 haploinsufficiency [8]. SIRT1 is one of the many genes altered by BRCA1 haploinsufficiency [3][5]. This protein-deacetylase is involved in various cellular processes [10][11] including DNA damage repair and telomere maintenance [12][13][14]. In addition, SIRT1 is a critical modulator of G4/BER-mediated transcription by deacetylating APE1[15][16], and its own expression is regulated by a G4/BER-mediated mechanism [17][18]. Therefore, SIRT1 is a significant feedback factor that affects G4/BER-mediated transcriptional regulation and phenotype. SIRT1 is known to have an important and unique association with BRCAness tumors. Its expression level has been reported to increase in a number of tumor types [10][19]; however, some cancers, such as breast and ovarian, show down-regulated levels of SIRT1 [20][21]. The effects of SIRT1 on promoting senescence or negatively regulating its own expression in cells are known to depend on the presence or absence of p53 [10]. It has yet to be elucidated whether SIRT1 down regulation and a high frequency of TP53 mutations in BRCA1-associated tumors are correlated. However, it has been clearly demonstrated that BRCA1-deficient breast cancers have lower levels of SIRT1 than the corresponding normal controls, and the ectopic expression of SIRT1 has been reported to inhibit BRCA1 mutant cell growth and tumor formation in a mouse model, but not in the BRCA1 wild-type [20].
In addition to SIRT1, BRCA1 deficiency alters the expression of many other factors that can affect G4/BER-mediated transcription, such as NRF2, CYP1A1, RANKL, OGG1, and APE1. Primary mammary epithelial cells from BRCA1-deficient mice show low levels of Nrf2 expression, a master regulator of the cellular antioxidant response, and Nrf2-transcriptional targeted antioxidant enzymes [22]. They determine the ROS levels and redox status in cells which influence the oxidation of guanine and G4 folding. BRCA1 also regulates estrogen metabolism-mediated DSB by repressing the transcription of estrogen-metabolizing enzymes such as CYP1A1 in breast cells [23]. Regardless of the estrogen receptor status, estrogen release can cause damage and genomic instability via catechol estrogen metabolites [24][25]. Tissue-specific conversion to catechol estrogen metabolites, along with the subsequent formation of ROS and unstable catechol estrogen intermediates, was one of the early explanations for tissue-specific tumorigenesis due to BRCA1 deficiency in estrogen responsive tissue [24]. In addition, BRCA1 haploinsufficiency upregulates RANKL expression and cell proliferation [26], which contributes significantly to TNBC tumorigenesis from the cell-of-origin [27][28], and RANKL inhibition markedly attenuates tumor onset [29][30]. BRCA1 also regulates the transcription of major BER enzymes, such as OGG1 and APE1 [31].
It is not yet known whether altered expression of these genes by BRCA1 haploinsufficiency is cell type-specific and whether such an alteration in the expression of a certain gene contributes to a cell-type-specific phenotype. However, these suggest that defects in resolving transcriptional regulatory G4s cause transcriptional alterations in many genes, among which a certain gene, such as SIRT1 [12][13][14], may be associated with a cell type-specific phenotype as a context-dependent cancer driver.

3. BRCA1 Insufficiency Causes Multi-Level Heterogeneous Molecular and Cellular Alterations

BRCA1 heterozygosity can cause sequential conditional haploinsufficiency in the following three distinct functions of BRCA1. First, BRCA1 haploinsufficiency for processing G4s may result in altered gene expression even before malignant tumor onset in BRCA1 mutation carriers [2][3]. Second, if BRCA1 deficiency becomes more severe, stalled replication forks will accumulate and repair may not be sufficient [145]. Third, once BRCA1 haploinsufficiency results in defective SFR, the impaired stalled forks can leave more deleterious DSBs [32] and CNVs by non-HR repair mechanism [33]. That is, a severe accumulation of G4s can induce conditional haploinsufficiency for SFR or HR-DSB repair sequentially leading to genomic instability. In addition to the conditional haploinsufficiency for SFR and HR-DSB, the altered expression of certain genes, such as SIRT1 [12][13][14], further contributes to genomic instability.
In addition to transcriptional alteration and genomic damage, the dysregulation of the transcriptional regulatory G4s can cause epigenetic alterations, including changes of histone marks and DNA methylation pattern. First, poor G4 processing during replication leads to epigenetic instability in which epigenetic chromatin marks are not well transmitted to daughter cells (see [34] and references therein). This is because the DNA helicase and polymerase are uncoupled as the helicase continues to unwind the parental duplex, even when the leading strand polymerase encounters a persistent G4 structure and is blocked. Delayed replication of excessive single strand DNAs between the helicase and the polymerase results in loss of parental histones that can be recycled during reestablishment of chromatin. Parental histone recycling is important for maintaining the parental expression status by propagating parental histone marks to newly formed chromatin after replication [34].
In the other hand, DNA G4 structures mold the DNA methylome by sequestering DNMT1 and locally inhibiting methylation at specific CpG islands [35]. In addition to regulating DNMT1 transcription [36], this means that BRCA1 influences location-specific, genome-wide methylation landscape by regulating G4s. This may account for the epigenetic alterations such as a lower methylation level in CpG island promoters, observed in BRCA1 deficient tumors [36][37][38][39]. Furthermore, the fact that unresolved G4s contribute to both hypomethylation and DNA damage is also consistent with the existing correlation between the breakpoints in chromosomal rearrangements and DNA methylation patterns in breast cancer [40] and HGSC [41]. In breast cancer cells, chromosomal breakpoint intervals colocalize with differentially methylated regions [40]. For HGSC, global DNA hypomethylation (+) tumors had significantly higher levels of chromosomal instability than global DNA hypomethylation (−) tumors, and notably, CNVs were enriched in hypomethylated blocks [41]. The role of the G4 structure as a mediator of epigenetic modification was recently documented in another review [42][43].

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