The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells.
The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells.
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DOI：
10.1016/j.stemcr.2015.04.006
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发表时间：
2015-06-09
影响因子：
5.9
通讯作者：
Brack, Andrew S.
中科院分区：
文献类型：
--
作者：
Kollu, Swapna;Abou-Khalil, Rana;Shen, Carl;Brack, Andrew S.
为了确保准确的基因组分离，细胞进化出纺锤体组装检查点（SAC），其在成体干细胞中的作用尚不清楚。骨骼肌干细胞中SAC激酶Mps1及其下游效应物Mad2的诱导扰动表明，SAC对正常肌肉生长、修复和干细胞库的自我更新至关重要。sac缺陷肌肉干细胞在细胞周期的G1期停滞，非整倍体升高，即使在诱导条件下也难以分化。p21CIP1负责这些sac缺陷表型。尽管非整倍体与衰老相关，但我们发现衰老的增殖肌肉干细胞显示出强大的SAC活性，而非整倍体并未升高。因此，肌肉干细胞有两步机制来保护它们的基因组完整性。SAC可防止染色体错分离，如果失败，依赖p21cip1的G1阻滞会限制细胞繁殖和组织整合。这些机制确保基因组受损的肌肉干细胞不会促进组织稳态。肌肉干细胞中纺锤体组装检查点（SAC）基因的激活导致G1阻滞，提高非整倍性，并阻断分化。G1阻滞是通过p53/p21途径介导的。年老小鼠激活的肌肉干细胞具有强健的纺锤体组装检查点（SAC）。肌肉干细胞中SAC的遗传破坏促进非整倍体，通过p53/p21介导的可逆细胞周期阻滞来阻止分化。尽管SAC在肌肉生长和修复中起着关键作用，但衰老的肌肉干细胞具有强大的SAC活性。
To ensure accurate genomic segregation, cells evolved the spindle assembly checkpoint (SAC), whose role in adult stem cells remains unknown. Inducible perturbation of a SAC kinase, Mps1, and its downstream effector, Mad2, in skeletal muscle stem cells shows the SAC to be critical for normal muscle growth, repair, and self-renewal of the stem cell pool. SAC-deficient muscle stem cells arrest in G1 phase of the cell cycle with elevated aneuploidy, resisting differentiation even under inductive conditions. p21CIP1 is responsible for these SAC-deficient phenotypes. Despite aneuploidy’s correlation with aging, we find that aged proliferating muscle stem cells display robust SAC activity without elevated aneuploidy. Thus, muscle stem cells have a two-step mechanism to safeguard their genomic integrity. The SAC prevents chromosome missegregation and, if it fails, p21CIP1-dependent G1 arrest limits cellular propagation and tissue integration. These mechanisms ensure that muscle stem cells with compromised genomes do not contribute to tissue homeostasis. Activation turns on spindle assembly checkpoint (SAC) genes in muscle stem cells SAC failure leads to G1 arrest, raises aneuploidy, and blocks differentiation G1 arrest is mediated through the p53/p21 pathway Activated muscle stem cells from aged mice possess a robust SAC In this article, Brack and colleagues examine the spindle assembly checkpoint (SAC) in skeletal muscle stem cells. Genetic disruption of the SAC in muscle stem cells promotes aneuploidy, invoking a reversible cell-cycle arrest mediated through p53/p21 to prevent differentiation. Despite the critical role of the SAC for muscle growth and repair, aged muscle stem cells possess robust SAC activity.
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DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1242/dev.100842
发表时间：
2014-04
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Chakkalakal JV;Christensen J;Xiang W;Tierney MT;Boscolo FS;Sacco A;Brack AS
通讯作者：
Brack AS
影响因子：
56.9
作者：
HALEVY, O;NOVITCH, BG;LASSAR, AB
通讯作者：
LASSAR, AB
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
64.5
作者：
GU, W;SCHNEIDER, JW;NADALGINARD, B
通讯作者：
NADALGINARD, B