Human cancer cells commonly acquire DNA damage during mitotic arrest.
The mitotic checkpoint is a mechanism that arrests the progression to anaphase until all chromosomes have achieved proper attachment to mitotic spindles. In cancer cells, satisfaction of this checkpoint is frequently delayed or prevented by various defects, some of which have been causally implicated in tumorigenesis. At the same time, deliberate induction of mitotic arrest has proved clinically useful, as antimitotic drugs that interfere with proper chromosome-spindle interactions are effective anticancer agents. However, how mitotic arrest contributes to tumorigenesis or antimitotic drug toxicity is not well defined. Here, we report that mitotic chromosomes can acquire DNA breaks during both pharmacologic and genetic induction of mitotic arrest in human cancer cells. These breaks activate a DNA damage response, occur independently of cell death, and subsequently manifest as karyotype alterations. Such breaks can also occur spontaneously, particularly in cancer cells containing mitotic spindle abnormalities. Moreover, we observed evidence of some breakage in primary human cells. Our findings thus describe a novel source of DNA damage in human cells. They also suggest that mitotic arrest may promote tumorigenesis and antimitotic toxicity by provoking DNA damage.
Dalton
W Brian
WB
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nandan
Mandayam O
MO
Moore
Ryan T
RT
Yang
Vincent W
VW
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008938:Mitosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones