MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells.
MutSβ and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells.
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DOI：
10.1093/nar/gks810
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发表时间：
2012-11-01
影响因子：
14.9
通讯作者：
Lahue RS
中科院分区：
文献类型：
--
作者：
Gannon AM;Frizzell A;Healy E;Lahue RS
三核苷酸重复 (TNR) 扩增会导致至少 17 种遗传性神经系统疾病，包括亨廷顿舞蹈病。扩增被认为是由特定反式作用蛋白对 TNR DNA 的异常加工引起的。例如，小鼠体内需要 DNA 修复复合物 MutSβ（MSH2-MSH3 异二聚体）来持续扩展长的致病等位基因。 TNR 扩展的一个显着特征是阈值效应，即重复单元范围狭窄（人类约为 30-40），在此范围内突变频率急剧上升并可能引发疾病。本研究的目的是确定促进人星形细胞系中 CTG•CAG 重复阈值长度扩展的因素。 MutSβ 亚基 MSH2 或 MSH3 的 siRNA 敲低阻碍了阈值长度重复的扩展，而 MutSα 亚基 MSH6 的敲低则没有效果。染色质免疫沉淀实验表明，TNR 处富集了 MutSβ，但没有富集 MutSα。这些发现表明 MutSβ 在促进阈值长度 CTG·CAG 束的扩张中具有直接作用。我们将 II 类脱乙酰酶 HDAC5 确定为一种新型的扩增促进因子，加入了之前确定的 I 类脱乙酰酶 HDAC3 的行列。双重敲低与 MutSβ、HDAC3 和 HDAC5 通过共同途径促进阈值长度 TNR 扩展的可能性一致。
Trinucleotide repeat (TNR) expansions cause at least 17 heritable neurological diseases, including Huntington’s disease. Expansions are thought to arise from abnormal processing of TNR DNA by specific trans-acting proteins. For example, the DNA repair complex MutSβ (MSH2–MSH3 heterodimer) is required in mice for on-going expansions of long, disease-causing alleles. A distinctive feature of TNR expansions is a threshold effect, a narrow range of repeat units (∼30–40 in humans) at which mutation frequency rises dramatically and disease can initiate. The goal of this study was to identify factors that promote expansion of threshold-length CTG•CAG repeats in a human astrocytic cell line. siRNA knockdown of the MutSβ subunits MSH2 or MSH3 impeded expansions of threshold-length repeats, while knockdown of the MutSα subunit MSH6 had no effect. Chromatin immunoprecipitation experiments indicated that MutSβ, but not MutSα, was enriched at the TNR. These findings imply a direct role for MutSβ in promoting expansion of threshold-length CTG•CAG tracts. We identified the class II deacetylase HDAC5 as a novel promoting factor for expansions, joining the class I deacetylase HDAC3 that was previously identified. Double knockdowns were consistent with the possibility that MutSβ, HDAC3 and HDAC5 act through a common pathway to promote expansions of threshold-length TNRs.
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影响因子：
64.8
作者：
Kovtun, Irina V.;Liu, Yuan;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
6.1
作者：
Dragileva, Ella;Hendricks, Audrey;Teed, Allison;Gillis, Tammy;Lopez, Edith T.;Friedberg, Errol C.;Kucherlapati, Raju;Edelmann, Winfried;Lunetta, Kathryn L.;MacDonald, Marry E.;Wheeler, Vanessa C.
通讯作者：
Wheeler, Vanessa C.
影响因子：
8
作者：
Bruton, R. K.;Rasti, M.;Grand, R. J. A.
通讯作者：
Grand, R. J. A.
DOI：
10.1073/pnas.1105461108
发表时间：
2011-10-18
影响因子：
11.1
作者：
Lang, Walter H.;Coats, Julie E.;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.