Regulation of the Intranuclear Distribution of the Cockayne Syndrome Proteins.
Regulation of the Intranuclear Distribution of the Cockayne Syndrome Proteins.
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调节Cockayne综合征蛋白的核内分布。
DOI：
10.1038/s41598-018-36027-6
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发表时间：
2018-11-30
影响因子：
4.6
通讯作者：
Wilson DM 3rd
中科院分区：
文献类型：
--
作者：
Iyama T;Okur MN;Golato T;McNeill DR;Lu H;Hamilton R;Raja A;Bohr VA;Wilson DM 3rd
Cockayne综合征(CS)是一种遗传性疾病，涉及光敏、发育缺陷、进行性退化和过早衰老的特征。有证据表明，主要的CS蛋白CsA和CSB主要在核中发挥作用，特别是在DNA修复和RNA转录中。我们在这里揭示了CSB靶向的一个复杂的调控，它涉及三个主要的共识信号：NLS1(aa467-481)，它与NoLS1(aa302-341)合作指导核和核仁的定位；以及NLS2(aa1038-1055)，似乎优化了核浓缩。CSB在核仁的定位也被发现对UVC的完全抵抗很重要。CSA不包含任何明显的靶向序列，任何形式的截断都会对CSA产生不利影响(即可能会破坏其稳定性)。没有观察到CsA和CSB的亚核定位之间的相互协调，这意味着这一方面不是CS的临床特征的基础。CsA的E3泛素连接酶结合伙伴DDB1在CsA和DDB2的稳定性中起着重要作用，促进了CsA在紫外线照射后与染色质的结合，但不影响CSB染色质的结合。我们还观察到，CSB最初在核质和核仁中对DNA链间交联的募集是相似的，尽管在前者的最终积累更大。虽然CSB在核仁DNA损伤部位的组装不受RNA聚合酶I抑制的影响，但在这些假定修复的部位的稳定保留被取消。我们的研究揭示了对CsA和CSB核内动力学的多方面调节，这在调节它们的细胞功能方面发挥了作用。
Cockayne syndrome (CS) is an inherited disorder that involves photosensitivity, developmental defects, progressive degeneration and characteristics of premature aging. Evidence indicates primarily nuclear roles for the major CS proteins, CSA and CSB, specifically in DNA repair and RNA transcription. We reveal herein a complex regulation of CSB targeting that involves three major consensus signals: NLS1 (aa467-481), which directs nuclear and nucleolar localization in cooperation with NoLS1 (aa302-341), and NLS2 (aa1038-1055), which seemingly optimizes nuclear enrichment. CSB localization to the nucleolus was also found to be important for full UVC resistance. CSA, which does not contain any obvious targeting sequences, was adversely affected (i.e. presumably destabilized) by any form of truncation. No inter-coordination between the subnuclear localization of CSA and CSB was observed, implying that this aspect does not underlie the clinical features of CS. The E3 ubiquitin ligase binding partner of CSA, DDB1, played an important role in CSA stability (as well as DDB2), and facilitated CSA association with chromatin following UV irradiation; yet did not affect CSB chromatin binding. We also observed that initial recruitment of CSB to DNA interstrand crosslinks is similar in the nucleoplasm and nucleolus, although final accumulation is greater in the former. Whereas assembly of CSB at sites of DNA damage in the nucleolus was not affected by RNA polymerase I inhibition, stable retention at these sites of presumed repair was abrogated. Our studies reveal a multi-faceted regulation of the intranuclear dynamics of CSA and CSB that plays a role in mediating their cellular functions.
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影响因子：
16
作者：
Lake, Robert J.;Geyko, Anastasia;Fan, Hua-Ying
通讯作者：
Fan, Hua-Ying
影响因子：
64.5
作者：
Iben, S;Tschochner, H;Grummt, I
通讯作者：
Grummt, I
影响因子：
14.9
作者：
Berquist BR;Canugovi C;Sykora P;Wilson DM 3rd;Bohr VA
通讯作者：
Bohr VA
影响因子：
5.3
作者：
Citterio, E;Van Den Boom, V;Vermeulen, W
通讯作者：
Vermeulen, W
影响因子：
14.9
作者：
Aydin, Ozge Z.;Marteijn, Jurgen A.;Lans, Hannes
通讯作者：
Lans, Hannes