MOF suppresses replication stress and contributes to resolution of stalled replication forks

Dharmendra Kumar Singh, Raj K. Pandita, Mayank Singh, Sharmistha Chakraborty, Shashank Hambarde, Deepti Ramnarain, Vijaya Charaka, Kazi Mokim Ahmed, Clayton R. Hunt, Tej K. Pandita

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2 Scopus citations

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.

Original languageEnglish (US)
Article numbere00484-17
JournalMolecular and Cellular Biology
Volume38
Issue number6
DOIs
StatePublished - Mar 1 2018

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Keywords

  • Homologous recombination
  • MOF
  • PCNA
  • R loop
  • Replication stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Singh, D. K., Pandita, R. K., Singh, M., Chakraborty, S., Hambarde, S., Ramnarain, D., Charaka, V., Ahmed, K. M., Hunt, C. R., & Pandita, T. K. (2018). MOF suppresses replication stress and contributes to resolution of stalled replication forks. Molecular and Cellular Biology, 38(6), [e00484-17]. https://doi.org/10.1128/MCB.00484-17