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Heme oxygenase-1 protects cells from replication stress
Patryk Chudy1, Jakub Kochan2, Mateusz Wawro2
1Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland.
Redox Biology
|July 24, 2024
Summary
Heme oxygenase-1 (HO-1) protects cells from replication stress by removing DNA G-quadruplexes. Its absence leads to DNA damage and impaired p53 function.
Area of Science:
- Cellular Biology
- DNA Replication
- Molecular Mechanisms
Background:
- Heme oxygenase-1 (HO-1) degrades heme, preventing oxidative damage.
- Heme stabilizes G-quadruplexes, which can hinder DNA replication.
- Nuclear HO-1 has been shown to interact with and remove G-quadruplexes.
Purpose of the Study:
- To investigate the role of HO-1 in safeguarding cells against replication stress.
- To determine if HO-1 deficiency exacerbates replication stress due to G-quadruplex accumulation.
- To elucidate the molecular mechanisms underlying HO-1's protective function.
Main Methods:
- Utilized control and HMOX1-deficient HEK293T cell lines.
- Employed immunostaining to detect G-quadruplexes.
- Performed fiber assays to analyze replication fork progression and stalling.
- Isolated hematopoietic stem cells from Hmox1 knockout mice.
- Analyzed lymphoblastoid cell lines from an HMOX1-deficient patient.
Main Results:
- DNA G-quadruplexes accumulated in HO-1 deficient cells, exacerbated by δ-aminolevulinic acid (ALA).
- Replication stress, evidenced by stalled forks, increased in the absence of HO-1.
- HO-1 deficiency impaired p53 nuclear import and accumulation, affecting the PARP1-p53-p21 axis.
- ALA administration proved a specific method for increasing intracellular heme.
Conclusions:
- HO-1 plays a crucial role in protecting cells against replication stress.
- The cytoprotective activity of HO-1 is linked to its ability to manage G-quadruplexes and maintain DNA replication integrity.
- HO-1 deficiency compromises DNA replication fidelity through impaired p53 regulation.
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