Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis.
BACKGROUND
In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established.


RESULTS
Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof¹/+; mnkp⁶/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks.


CONCLUSIONS
mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using Drosophila as model system and carry out the interaction of MOF with the known components of the DNA damage pathway.
Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad 500607, India.
Sreerangam N C V L
SN
Pushpavalli
Arpita
A
Sarkar
M Janaki
MJ
Ramaiah
Debabani Roy
DR
Chowdhury
Utpal
U
Bhadra
Manika
M
Pal-Bhadra
D000818:Animals; D059447:Cell Cycle Checkpoints; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology* / Q000201:enzymology / Q000235:genetics*; D047108:Embryonic Development; D005260:Female; D042822:Genomic Instability; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008938:Mitosis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D009687:Nuclear Proteins; D051548:Histone Acetyltransferases; C111063:mof protein, Drosophila; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases