The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model.
Allelic variants of CHEK2 contribute to an elevated risk for human breast cancer and possibly other cancer types. In particular, the CHEK2*1100delC polymorphic variant has been identified as a low-penetrance breast cancer susceptibility allele in breast cancer families with wild type BRCA1 and BRCA2. To better understand the molecular basis by which this allele increases risk for disease, we have generated a mouse in which the wild type CHEK2 (Chk2 in mouse) allele has been replaced with the 1100delC variant. Mouse embryo fibroblasts (MEFs) derived from these mice have an altered cell cycle profile in which a far greater proportion of cells are in S-phase and in G2 (4N) compared with wild type cells. The mutant cells show signs of spontaneous genomic instability as indicated by polyploidy and an increase in DNA double strand breaks.
Bahassi
El Mustapha
el M
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Penner
C Gail
CG
Robbins
Susan B
SB
Tichy
Elisia
E
Feliciano
Estrella
E
Yin
Moying
M
Liang
Li
L
Deng
Li
L
Tischfield
Jay A
JA
Stambrook
Peter J
PJ
D000483:Alleles; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006720:Homozygote; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases