TY - JOUR
T1 - MOF suppresses replication stress and contributes to resolution of stalled replication forks
AU - Singh, Dharmendra Kumar
AU - Pandita, Raj K.
AU - Singh, Mayank
AU - Chakraborty, Sharmistha
AU - Hambarde, Shashank
AU - Ramnarain, Deepti
AU - Charaka, Vijaya
AU - Ahmed, Kazi Mokim
AU - Hunt, Clayton R.
AU - Pandita, Tej K.
N1 - Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Homologous recombination
KW - MOF
KW - PCNA
KW - R loop
KW - Replication stress
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U2 - 10.1128/MCB.00484-17
DO - 10.1128/MCB.00484-17
M3 - Article
C2 - 29298824
AN - SCOPUS:85042558425
SN - 0270-7306
VL - 38
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 6
M1 - e00484-17
ER -