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ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress
Yu-Ching Teng1, Aishwarya Sundaresan1, Ryan O'Hara1
1Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, Children's Medical Center Research Institute, Harold. C. Simmons Comprehensive Cancer Center, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Abstract:
ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.
Insights
ATRX loss causes G-quadruplex (G4) DNA structures to accumulate, leading to replication stress. ATRX
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- ATRX is a tumor suppressor linked to DNA replication stress.
- Its role in resolving G-quadruplex (G4) DNA structures during replication is unclear.
- Loss of ATRX sensitizes cells to G4 structure stabilizers.
Purpose of the Study:
- To elucidate the molecular function of ATRX at G4 regions during DNA replication.
- To understand how ATRX loss impacts genome stability and contributes to disease.
Main Methods:
- Investigated ATRX association with MCM replication complex subunits.
- Analyzed G4 structure accumulation in newly synthesized DNA upon ATRX loss.
- Assessed the roles of ATRX helicase domain and H3.3 chaperone function.
- Examined the relationship between ATRX, ESET, heterochromatin formation, and G4-mediated stress.
Main Results:
- ATRX interacts with MCM replication complex subunits.
- ATRX loss results in G4 structure accumulation at newly synthesized DNA.
- Both ATRX helicase activity and H3.3 chaperone function are crucial for preventing G4-induced replication stress.
- ATRX function precedes ESET-mediated heterochromatin formation, a key protective event.
- Tumors with ATRX or ESET mutations exhibit increased mutation burden at G4-rich sequences.
Conclusions:
- ATRX directly participates in resolving G4 structures during DNA replication.
- ATRX's functions are essential for maintaining genome stability by preventing G4-mediated replication stress.
- Understanding ATRX's role offers insights into ATRX-mutated cancers and associated genomic instability.
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