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Sam68 stimulates Theta-Mediated End-Joining by suppressing poison exon inclusion in Polq mRNA

ABSTRACT: DNA polymerase Theta-Mediated End-Joining (TMEJ) is a stand-alone mutagenic DNA double-strand break (DSB) repair pathway that becomes critical when high-fidelity repair is compromised. Although the enzymatic mechanism of TMEJ has been extensively studied in recent years, its regulation remains poorly understood. Here, we identify and characterize the RNA-binding protein Sam68 (also known as Khdrbs1) as a key modulator of TMEJ in mammalian cells. We demonstrate that Sam68 is required for proper expression of Polq, the gene encoding polymerase theta (Polθ), the central factor in TMEJ. Loss of Sam68 results in reduced TMEJ at CRISPR-induced DSBs and increased sensitivity to ionizing radiation. Mechanistically, Sam68 promotes correct splicing of Polq mRNA by suppressing the inclusion of a conserved poison exon that introduces a premature termination codon in the transcript. This function depends on the RNA-binding domain of Sam68. Genetic deletion of the poison exon restores Polq expression and rescues TMEJ activity in Sam68-depleted cells. Together, these findings establish alternative splicing as a direct mechanism controlling TMEJ capacity and reveal a conserved regulatory mechanism that tunes mutagenic DSB repair through modulation of Polθ abundance.

ORGANISM(S): Mus musculus

PROVIDER: GSE324893 | GEO | 2026/07/24

REPOSITORIES: GEO

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Sam68 stimulates Theta-Mediated End-Joining by suppressing poison exon inclusion in Polq mRNA

Project description:Sam68 stimulates Theta-Mediated End-Joining by suppressing poison exon inclusion in Polq mRNA

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Sam68 insures proper 3'-end pre-mRNA processing during germ cell differentiation

Project description:Male germ cells express the widest repertoire of transcript variants in mammalian tissues. Nevertheless, factors and mechanisms underlying such pronounced diversity are largely unknown. The splicing regulator Sam68 is highly expressed in meiotic cells and its ablation results in defective spermatogenesis. Herein, we uncover an extensive splicing program operated by Sam68 across meiosis, primarily characterized by alternative last exon (ALE) regulation in genes of functional relevance for spermatogenesis. Lack of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites.

2019-03-12 | GSE122929 | GEO

SAM68-specific splicing is required for proper selection of alternative 3'UTR isoforms in the nervous system

Project description:Neuronal alternative splicing is dynamically regulated in a spatiotemporal fashion. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs governed by STARs remains unclear. We deciphered the alternative splicing programs of SAM68 and SLM1 proteins using transcriptomics. We reveal that SAM68 and SLM1 encode distinct alternative splicing programs; SAM68 preferentially controls alternative last exon (ALE) splicing. Interleukin 1-receptor accessory protein (Il1rap) is a novel target for SAM68. The usage of Il1rap ALEs results in mainly two variants encoding two functionally different isoforms, a membrane-bound (mIL1RAcP) and a soluble (sIL1RAcP) type. The brain exclusively expresses mIL1RAcP. SAM68 knockout results in remarkable conversion into sIL1RAcP in the brain, which significantly disturbs IL1RAcP neuronal function. Thus, we uncover the critical role of proper neuronal isoform selection through ALE choice by the SAM68-specific splicing program.

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NeonGreen-POLQ knock-in in Human embryonic kidney 293 cells VS Human embryonic kidney 293 cells

Project description:Replication stress (RS) can lead to the formation of DNA double strand breaks (DSBs) and threatens genomic stability. Homologous recombination (HR) pathway is essential to prevent RS and repairs associated DSBs. Upon excessive RS or HR deficiency, DSBs can persist in mitosis, wherein DNA damage response and DSB repair are inhibited. Thus, the fate of DSBs remaining or arising in mitosis remains poorly understood. Here we unwind two distinct roles of the polymerase theta (Polθ) in the maintenance of genomic stability. First, by mass spectrometry and foci screening we show that, in interphase, Polθ interacts with HR proteins and its recruitment to IR-induced DSBs is highly dependent of HR pathway. Secondly, we identify a novel role of the Polθ in counteracting the deleterious effect of DSBs in mitosis. Contrariwise to its interphase recruitment, Polθ recruitment to mitotic DSBs is HR-independent and triggered by mitotic kinases activities. In response to RS or HR deficiency, Polθ localizes to DSBs throughout mitosis and forms nuclear bodies in the G1 daughter cells. In addition, Polθ localizes to centromeres and acentric fragments and activates the mitotic checkpoint. Conversely, Polθ deficiency leads to premature anaphase onset, resulting in an accumulation of mitotic abnormalities. Strikingly, the specific inhibition of Polθ in mitosis kills HR-deficient cells, identifying mitotic Polθ function as its key role in maintaining genome integrity. Our results pinpoint to the mitotic Polθ-mediated replication stress response pathway as a unique vulnerability of cancer cells, with great potential for further investigation.

2023-09-18 | PXD029585 | Pride

SAM68 is a splicing regulator in triple negative breast cancer

Project description:SAM68 is an RNA binding protein frequently up-regulated in several human cancers and its oncogenic activity has often been associated with its splicing activity. Nevertheless, the genome-wide impact of SAM68 on the transcriptome of cancer cells is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 SAM68-silenced cells, we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this splicing factor.

2022-04-04 | GSE140754 | GEO

Sam68 regulation of alternative splicing in the developing cerebellum

Project description:We uncover a Sam68-dependent splicing program during cerebellar development. These events direct proper isoform expression of the genes required to guarantee the establishment of the correct spatial/temporal neural circuitry. The dysregulation in Sam68 null mice leads to functional defects in adult neurons

2020-06-01 | GSE133711 | GEO

SAM68 is a crucial post-transcriptional regulator of cardiogenesis

Project description:RNA-binding proteins (RBPs) of the STAR family play important roles in mammalian development, yet their precise contributions to lineage specification remain incompletely understood. Here, using CRISPR–Cas9 knockout models combined with multi-omics approaches, we investigate the roles of two STAR proteins, SAM68 and QKI, in mouse embryonic stem cells (mESCs). Both RBPs contribute to mESC proliferation, self-renewal, and efficient differentiation into cardiomyocytes. Our data support a role for QKI in the regulation of cardiac differentiation programs. In addition, our analyses reveal a previously underappreciated contribution of SAM68 to cardiomyocyte specification, acting through multiple post-transcriptional mechanisms. Despite belonging to the same protein family, SAM68 and QKI regulate largely distinct post-transcriptional programs during differentiation. Specifically, SAM68 modulates alternative splicing and promotes the biogenesis of a subset of cardiac-enriched circular RNAs through binding to intronic regions flanking back-splice sites and association with NF90/110. In addition, SAM68 associates with untranslated regions of key differentiation-related transcripts, including Gata4 mRNA, a key transcription factor regulating cardiogenesis, and likely functions in complex with other RNA-binding proteins to regulate these transcripts. Together, these findings identify SAM68 as a regulator of multiple RNA processing pathways contributing to cardiomyocyte differentiation and provide insight into how STAR proteins shape post-transcriptional gene regulatory networks during early development.

2026-04-02 | GSE326251 | GEO

SAM68 promotes Lung adenocarcinoma tumorigenesis by regulating cancer metabolic conversion through alternative splicing

Project description:The metabolic conversion of oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling the tumor metabolic switch is still not entirely clear. Here we demonstrate that SAM68 (gene name: KHDRBS1) as a splicing regulatory factor is frequently overexpressed in Lung adenocarcinoma (LUAD) and negatively correlated with the prognosis of LUAD patients. we find SAM68 promotes LUAD cells tumorigenesis and metastasis both in vitro and in vivo by regulating cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of Pyruvate kinase (PKM) pre-mRNAs, finally promoting the formation of PKM2. Mechanically, Sam68 interacted with the splicing repressor hnRNP A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated the PKM splicing regulation. Together, our work demonstrates key roles of SAM68 in the cancer metabolic conversion by regulating alternative splicing and SAM68 may be a promising therapeutic target for treating LUAD.This project looks into how SAM68 levels affect cancer cell phenotype in vitro

2020-11-04 | GSE149120 | GEO

Gene expression profiles affected by Sam68-knockdown in oral squamous cell carcinoma cells

Project description:The changes in the transcriptome via Sam68-knockdown were investigated in oral squamous cell carcinoma cells. The candidate genes which are regulated by Sam68 were demonstrated.

2022-07-28 | GSE202136 | GEO

Recombination initiation maps of individual human genomes

Project description:DNA double-strand breaks (DSBs) are introduced in meiosis to initiate recombination and to generate crossovers, the reciprocal exchanges of genetic material between parental chromosomes. Here we present the first high-resolution map of meiotic DSBs in individual human genomes. Comparing DSB maps between individuals shows that along with DNA binding by PRDM9, additional factors dictate the efficiency of DSB formation. Furthermore, we find that in human males, the frequency of DSB formation is the primary determinant of crossover rate. Patterns of sequence polymorphisms around meiotic DSB hotspots provide evidence for both GC-biased gene conversion and for a mutagenic role of DSB repair and/or recombination. Finally, we provide compelling evidence that the aberrant repair of meiotic DSBs is a driver of human genomic disorders. Detection of meiotic double strand breaks in testis of several human male individuals.

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