The BRCA1 gene codes for a protein involved in the DNA double strand break (DDSB) repair. Alongside the dominant full-length splicing form of BRCA1, numerous endogenously expressed alternative splicing variants of unknown significance have been described in various tissues. Some of them retain the original BRCA1 reading frame but lack several critical BRCA1 structural domains, suggesting an altered function of the resulting protein in the BRCA1-regulated processes. To characterize the effect of the BRCA1Δ14-15 splicing variant (with an in-frame deletion affecting the regulatory serine-containing domain) on the DDSB repair, we constructed the MCF-7 clones stably expressing the analyzed variant with/without a shRNA-mediated downregulation of the endogenous full-length wild-type BRCA1 expression. Our results show that the expression of the BRCA1Δ14-15 variant delays the γ-radiation-induced DDSB repair, alters the kinetics of irradiation-induced foci formation/decomposition and reduces the non-homologous end-joining capacity in MCF-7 cells. Therefore, the BRCA1Δ14-15 is not able to functionally replace the full-length wt BRCA1 in the DDSB repair. Our findings indicate that the endogenously expressed BRCA1 alternative splicing variants may negatively influence genome stability and support the growing evidence of the pathological potential of the sequence variants generated by an altered or misregulated alternative splicing in the process of mammary malignant transformation.
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http://dx.doi.org/10.1016/j.cellsig.2011.12.023 | DOI Listing |
RNA
December 2024
Instiute of Bioorganic Chemistry PAS
In this article, we present an approach to maximizing the splicing regulatory properties of splice-switching oligonucleotide (SSO) designed to regulate alternative splicing of PKM pre-mRNA. The studied SSO interacts with the regulatory element in exon 10 of PKM pre-mRNA and contributes to a significant reduction of PKM2 level with a simultaneous increase of the PKM1 isoform. This SSO forms a duplex not only with the regulatory fragment of exon 10 but also with a similar RNA fragment of intron 9.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Moores Cancer Center, University of California San Diego, San Diego, CA 92037, USA.
The discovery of tumor-derived neoantigens which elicit an immune response through major histocompatibility complex (MHC-I/II) binding has led to significant advancements in immunotherapy. While many neoantigens have been discovered through the identification of non-synonymous mutations, the rate of these is low in some cancers, including head and neck squamous cell carcinoma. Therefore, the identification of neoantigens through additional means, such as aberrant splicing, is necessary.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia.
Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by an array of mutations in the dystrophin gene, with the most commonly mutated regions being exons 48-55. One of the several existing approaches to treat DMD is gene therapy, based on alternative splicing and mutant exon skipping. Testing of such therapy requires animal models that carry mutations homologous to those found in human patients.
View Article and Find Full Text PDFExp Hematol
January 2025
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address:
T-cell acute lymphoblastic leukemia (T-ALL), which constitutes of 10-15% of all pediatric ALL cases, is known for its complex pathology due to pervasive genetic and chromosomal abnormalities. Although most children are successfully cured, chromosomal rearrangements involving the KMT2A gene is considered a poor prognostic factor. In a cohort of 171 pediatric T-ALL samples we have studied differences in gene and splice variant patterns in KMT2A rearranged (KMT2A-r) T-ALL compared to KMT2A negative (KMT2A-wt) T-ALL samples.
View Article and Find Full Text PDFCells
December 2024
Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
Alternative splicing is essential for the generation of various protein isoforms that are involved in cell differentiation and tissue development. In addition to internal coding exons, alternative splicing affects the exons with translation initiation codons; however, little is known about these exons. Here, we performed a systematic classification of human alternative exons using coding information.
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