TY - JOUR
T1 - The MUS81 endonuclease is essential for telomerase negative cell proliferation
AU - Zeng, Sicong
AU - Yang, Qin
N1 - Funding Information:
We thank Roger R. Reddel for providing the ALT cells, and Clare H. McGowan for providing the wild-type and mutant MUS81 constructs, MUS81 antibody and Mus81+/+ and Mus81-/- MEFs. This work is supported in part by grants from Concern Foundation (Q.Y.).
PY - 2009/7/15
Y1 - 2009/7/15
N2 - A substantial number of human tumors (~10%) are telomerase negative, and cells in such tumors have been proposed to maintain telomere length by the alternative lengthening of telomeres (ALT) pathway. Although details of the molecular mechanism of ALT are largely unknown, previous studies have shown that telomere homologous recombination (HR) is implicated in the ALT pathway. MUS81 is a DNA structure-specific recombination endonuclease and functions on aberrant DNA replication and recombination. Recently, we demonstrate that MUS81 plays a key role in the maintenance of telomeres in ALT cells (Zeng, et al. Nature Cell Biology, 2009). The MUS81 endonuclease specifically localizes to ALT-associated promyelocytic leukemia nuclear bodies (APBs) and interacts with telomeres in ALT cells. Depletion of MUS81 leads to reduced telomere recombination resulting in the growth arrest of ALT cells. The endonuclease activity of MUS81, regulated by its binding partner TRF2, is found to be essential for telomere post-replicative recombination. This study provides the first direct evidence that MUS81 specifically functions on ALT recombination-based cell survival. The specific function of MUS81 on the ALT pathway provides a potential powerful diagnostic marker and a therapeutic target for ALT tumors.
AB - A substantial number of human tumors (~10%) are telomerase negative, and cells in such tumors have been proposed to maintain telomere length by the alternative lengthening of telomeres (ALT) pathway. Although details of the molecular mechanism of ALT are largely unknown, previous studies have shown that telomere homologous recombination (HR) is implicated in the ALT pathway. MUS81 is a DNA structure-specific recombination endonuclease and functions on aberrant DNA replication and recombination. Recently, we demonstrate that MUS81 plays a key role in the maintenance of telomeres in ALT cells (Zeng, et al. Nature Cell Biology, 2009). The MUS81 endonuclease specifically localizes to ALT-associated promyelocytic leukemia nuclear bodies (APBs) and interacts with telomeres in ALT cells. Depletion of MUS81 leads to reduced telomere recombination resulting in the growth arrest of ALT cells. The endonuclease activity of MUS81, regulated by its binding partner TRF2, is found to be essential for telomere post-replicative recombination. This study provides the first direct evidence that MUS81 specifically functions on ALT recombination-based cell survival. The specific function of MUS81 on the ALT pathway provides a potential powerful diagnostic marker and a therapeutic target for ALT tumors.
KW - ALT
KW - APBs
KW - MUS81
KW - Telomere recombination
UR - http://www.scopus.com/inward/record.url?scp=68049114598&partnerID=8YFLogxK
U2 - 10.4161/cc.8.14.9149
DO - 10.4161/cc.8.14.9149
M3 - Review article
C2 - 19617716
AN - SCOPUS:68049114598
SN - 1538-4101
VL - 8
SP - 2157
EP - 2160
JO - Cell Cycle
JF - Cell Cycle
IS - 14
ER -