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Updated: Jun 8, 2025
CD Spectroscopy to Study DNA-Protein Interactions
Published on: February 10, 2022
Profound synthetic lethality between SMARCAL1 and FANCM
Sumin Feng1, Kaiwen Liu2, Jinfeng Shang2
1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
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 in human cells 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.
Insights
The combined loss of SMARCAL1 and FANCM ATPases causes severe genome instability. This highlights a crucial genetic buffering mechanism essential for maintaining genome integrity during DNA replication stress.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA replication stress threatens genome integrity.
- SNF2-family ATPases remodel DNA and proteins to mitigate this stress.
- Understanding these ATPases' roles in genome maintenance is crucial.
Purpose of the Study:
- Investigate the function of SNF2-type ATPases (SMARCAL1, ZRANB3, HLTF) in genome maintenance.
- Identify synthetic-lethal interactions involving these ATPases.
- Elucidate the mechanisms underlying genome instability.
Main Methods:
- CRISPR-based synthetic lethality screens in human cells.
- Analysis of genome instability and chromosome breakage.
- Focus on SNF2-type ATPases SMARCAL1, ZRANB3, and HLTF.
Main Results:
- SMARCAL1 exhibits a synthetic-lethal interaction with FANCM.
- Combined loss of SMARCAL1 and FANCM leads to severe genome instability.
- Chromosome breakage occurs at simple repeat loci that impede replication fork progression.
Conclusions:
- SMARCAL1 and FANCM form a critical genetic buffering mechanism.
- This interaction is essential for maintaining genome integrity under replication stress.
- Findings reveal a key pathway for preventing chromosome breakage.
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