Document Detail

DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint.
MedLine Citation:
PMID:  12419179     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: DNA damage during mitosis triggers an ATM kinase-mediated cell cycle checkpoint pathway in yeast and fly embryos that delays progression through division. Recent data suggest that this is also true for mammals. Here we used laser microsurgery and inhibitors of topoisomerase IIalpha to break DNA in various mammalian cells after they became committed to mitosis. We then followed the fate of these cells and emphasized the timing of mitotic progression, spindle structure, and chromosome behavior.
RESULTS: We find that DNA breaks generated during late prophase do not impede entry into prometaphase. If the damage is minor, cells complete mitosis on time. However, more significant damage substantially delays exit from mitosis in many cell types. In human (HeLa, CFPAC-1, and hTERT-RPE) cells, this delay occurs during metaphase, after the formation of a bipolar spindle and the destruction of cyclin A, and it is not dependent on a functional p53 pathway. Pretreating cells with ATM kinase inhibitors does not abrogate the metaphase delay due to chromosome damage. Immunofluorescence studies reveal that cells blocked in metaphase by chromosome damage contain one or more Mad2-positive kinetochores, and the block is rapidly overridden when the cells are microinjected with a dominant-negative construct of Mad2 (Mad2deltaC).
CONCLUSIONS: We conclude that the delay in mitosis induced by DNA damage is not due to an ATM-mediated DNA damage checkpoint pathway. Rather, the damage leads to defects in kinetochore attachment and function that, in turn, maintain the intrinsic Mad-2-based spindle assembly checkpoint.
Alexei Mikhailov; Richard W Cole; Conly L Rieder
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Current biology : CB     Volume:  12     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  2002 Oct 
Date Detail:
Created Date:  2002-11-06     Completed Date:  2003-05-01     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1797-806     Citation Subset:  IM    
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MeSH Terms
Cell Line
Cyclin A / metabolism
DNA Damage*
Enzyme Inhibitors / pharmacology
Fluorescent Antibody Technique, Indirect
Microscopy, Fluorescence
Piperazines / pharmacology
Spindle Apparatus*
Topoisomerase II Inhibitors
Grant Support
R37 GM040198/GM/NIGMS NIH HHS; R37 GM040198-19/GM/NIGMS NIH HHS; R37-40198//PHS HHS
Reg. No./Substance:
0/Cyclin A; 0/Enzyme Inhibitors; 0/Piperazines; 0/Topoisomerase II Inhibitors; 21416-68-2/4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione

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