Related Experiment Video
Updated: Feb 16, 2026
Direct Restart of a Replication Fork Stalled by a Head-On RNA Polymerase
Published on: April 29, 2010
MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks
Dharmendra Kumar Singh1, Raj K Pandita2, Mayank Singh3
1Department of Radiation Oncology, Weill Cornell Medical College, The Houston Methodist Research Institute, Houston, Texas, USA dksingh2006@gmail.com tpandita@houstonmethodist.org.
Abstract:
The human MOF (hMOF) protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation; however, its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted of MOF and under replicative stress induced by cisplatin, hydroxyurea, or camptothecin have reduced survival, a higher frequency of S-phase-specific chromosome damage, and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing. MOF interacted with PCNA, a key coordinator of replication and repair machinery at replication forks, and affected its ubiquitination and recruitment to the DNA damage site. Depletion of MOF, therefore, compromised the DNA damage repair response as evidenced by decreased Mre11, RPA70, Rad51, and PCNA focus formation, reduced DNA end resection, and decreased CHK1 phosphorylation in cells after exposure to hydroxyurea or cisplatin. These results support the argument that MOF plays an important role in suppressing replication stress induced by genotoxic agents at several stages during the DNA damage response.
Insights
The human MOF protein is crucial for cell survival under replication stress. MOF depletion impairs DNA damage repair, leading to genomic instability and reduced cell survival when exposed to genotoxic agents.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The human MOF (hMOF) protein, a MYST family histone acetyltransferase, is vital for transcription and DNA damage response.
- While essential for cell proliferation, hMOF's specific functions during DNA replication and replicative stress remain unclear.
Purpose of the Study:
- To investigate the role of hMOF in maintaining genomic stability during replication stress.
- To elucidate hMOF's involvement in DNA replication fork dynamics and DNA damage response pathways.
Main Methods:
- Depletion of hMOF using genetic methods.
- Induction of replicative stress using genotoxic agents (cisplatin, hydroxyurea, camptothecin).
- Analysis of cell survival, chromosome damage, R-loop formation, replication fork speed, origin firing, and DNA damage response markers (e.g., PCNA, Mre11, Rad51, CHK1).
Main Results:
- hMOF-depleted cells exhibited reduced survival, increased S-phase chromosome damage, and elevated R-loop formation under replicative stress.
- MOF depletion impaired replication fork speed, increased stalled forks, and affected new origin firing.
- hMOF interacts with PCNA, influencing its ubiquitination and recruitment to DNA damage sites, thereby compromising DNA damage repair signaling and execution.
Conclusions:
- hMOF plays a significant role in suppressing replication stress induced by genotoxic agents.
- MOF is essential for multiple stages of the DNA damage response, including replication fork maintenance and DNA repair.
- These findings highlight hMOF as a critical factor in maintaining genome integrity during DNA replication stress.
Related Concept Videos
02:37Restarting Stalled Replication Forks
02:37Restarting Stalled Replication Forks
01:02The DNA Replication Fork
01:02The DNA Replication Fork
02:40DNA Replication
Replication in Prokaryotes
DNA replication...
02:31Chromosome Replication