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ID 17113
file
creator
Hiyama, Takashi
Katsura, Mari
Yoshihara, Takashi
Kinomura, Aiko
Tonda, Tetsuji
Miyagawa, Kiyoshi
NDC
Medical sciences
abstract
The Mus81.Eme1 complex is a structure-specific endonuclease that preferentially cleaves nicked Holliday junctions, 3'-flap structures and aberrant replication fork structures. Mus81-/- mice have been shown to exhibit spontaneous chromosomal aberrations and, in one of two models, a predisposition to cancers. The molecular mechanisms underlying its role in chromosome integrity, however, are largely unknown. To clarify the role of Mus81 in human cells, we deleted the gene in the human colon cancer cell line HCT116 by gene targeting. Here we demonstrate that Mus81 confers resistance to DNA crosslinking agents and slight resistance to other DNA-damaging agents. Mus81 deficiency spontaneously promotes chromosome damage such as breaks and activates the intra-S-phase checkpoint through the ATM-Chk1/Chk2 pathways. Furthermore, Mus81 deficiency activates the G2/M checkpoint through the ATM-Chk2 pathway and promotes DNA rereplication. Increased rereplication is reversed by the ectopic expression of Cdk1. Haploinsufficiency of Mus81 orEme1 also causes similar phenotypes.These findings suggest that a complex network of the checkpoint pathways that respond to DNA doublestrand breaks may participate in some of the phenotypes associated with Mus81 or Eme1 deficiency.
journal title
Nucleic Acids Research
volume
Volume 34
issue
Issue 3
start page
880
end page
892
date of issued
2006
publisher
Oxford University Press
issn
0305-1048
ncid
publisher doi
pubmed id
language
eng
nii type
Journal Article
HU type
Journal Articles
DCMI type
text
format
application/pdf
text version
publisher
rights
Copyright (c) 2006 Oxford University Press.
relation url
department
Graduate School of Biomedical Science