Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Profound synthetic lethality between SMARCAL1 and FANCM (CRISPR screen)

ABSTRACT: DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens with three SNF2-type ATPases: SMARCAL1, ZRANB3 and HLTF. Here we show that SMARCAL1 displays a profound synthetic lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276441 | GEO | 2024/12/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Profound synthetic lethality between SMARCAL1 and FANCM (RNA-Seq)

Project description:DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens with three SNF2-type ATPases: SMARCAL1, ZRANB3 and HLTF. Here we show that SMARCAL1 displays a profound synthetic lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.

2024-12-24 | GSE276443 | GEO

Profound synthetic lethality between SMARCAL1 and FANCM (END-Seq)

2024-12-24 | GSE276442 | GEO

Profound synthetic lethality between SMARCAL1 and FANCM (RNA-Seq)

Project description:Profound synthetic lethality between SMARCAL1 and FANCM (RNA-Seq)

| PRJNA1157376 | ENA

Profound synthetic lethality between SMARCAL1 and FANCM (CRISPR screen)

Project description:Profound synthetic lethality between SMARCAL1 and FANCM (CRISPR screen)

| PRJNA1157381 | ENA

Profound synthetic lethality between SMARCAL1 and FANCM (END-Seq)

Project description:Profound synthetic lethality between SMARCAL1 and FANCM (END-Seq)

| PRJNA1157377 | ENA

SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion

Project description:Although genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy.

2024-01-24 | PXD046384 | Pride

Comprehensive Interrogation of Synthetic Lethality in the DNA Damage Response

Project description:The DNA damage response (DDR) is a multi-faceted network of pathways that preserves genome stability. Unraveling the complementary interplay between these pathways remains a challenge. Here, we comprehensively mapped genetic interactions for all core DDR genes using combinatorial CRISPRi screening. We discovered myriad new connections, including interactions between cancer genes and small molecule targets. We focused on two of the strongest interactions: FEN1/LIG1:WDR48 and FANCM:SMARCAL1. First, we found that WDR48 works with USP1 to restrain overactive translesion synthesis in FEN1/LIG1-deficient cells, and that a preclinical inhibitor of USP1 specifically kills FEN1-deficient cells. Second, we found that SMARCAL1 and FANCM suppress DNA double-strand break (DSB) formation at TA-rich repeats in late-replicating regions that otherwise escape into mitosis and cause nuclear fragmentation. Our dataset provides a springboard for further mechanistic investigations into connections between DDR factors and suggests multiple interactions that could be exploited in cancer therapy.

2025-02-03 | GSE236062 | GEO

The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription-replication conflicts

Project description:ATP-dependent chromatin remodelers are commonly mutated in human cancer. Mammalian SWI/SNF complexes comprise three conserved multi-subunit chromatin remodelers (cBAF, ncBAF and PBAF) that share the BRG1 (also known as SMARCA4) subunit responsible for the main ATPase activity. BRG1 is the most frequently mutated Snf2-like ATPase in cancer. Here we have investigated the role of SWI/SNF in genome instability, a hallmark of cancer cells, given its role in transcription, DNA replication and DNA damage repair. We show that depletion of BRG1 increases R-loops and R-loop-dependent DNA breaks, as well as transcription-replication conflicts. BRG1 colocalizes with R-loops and replication fork blocks, as determined by FANCD2 foci, with BRG1 depletion being epistatic to FANCD2 silencing. Our study, extended to other components of SWI/SNF, uncovers a key role of the SWI/SNF complex, in particular cBAF, in helping resolve R-loop-mediated transcription-replication conflicts; thus, unveiling a novel mechanism by which chromatin remodeling protects genome integrity.

2021-05-10 | GSE154631 | GEO

SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion [RNA-seq]

Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.

2024-01-22 | GSE245449 | GEO

SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion [CUT&RUN]

2024-01-22 | GSE245448 | GEO