TY - JOUR
T1 - The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair
AU - Van Oers, J. M.M.
AU - Edwards, Y.
AU - Chahwan, R.
AU - Zhang, W.
AU - Smith, C.
AU - Pechuan, X.
AU - Schaetzlein, S.
AU - Jin, B.
AU - Wang, Y.
AU - Bergman, A.
AU - Scharff, M. D.
AU - Edelmann, W.
N1 - Funding Information:
We thank Rani Sellers from the Einstein Histotechnology and Comparative Pathology facility for mouse pathology and for reviewing the manuscript. This study was supported by National Institutes of Health grants CA76329 and CA93484 (WE), and CA72649 and CA102705 (MDS). MDS is supported by the Harry Eagle Chair provided by the National Women’s Division of the Albert Einstein College of Medicine.
PY - 2014/7/24
Y1 - 2014/7/24
N2 - Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3 -/- mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared with p53 single mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3 -/- mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double-strand break repair (DSBR). Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy-number variation and a moderate microsatellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR. Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.
AB - Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3 -/- mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared with p53 single mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3 -/- mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double-strand break repair (DSBR). Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy-number variation and a moderate microsatellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR. Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.
UR - http://www.scopus.com/inward/record.url?scp=84905050986&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905050986&partnerID=8YFLogxK
U2 - 10.1038/onc.2013.365
DO - 10.1038/onc.2013.365
M3 - Article
C2 - 24013230
AN - SCOPUS:84905050986
SN - 0950-9232
VL - 33
SP - 3939
EP - 3946
JO - Oncogene
JF - Oncogene
IS - 30
ER -