Cold-inducible RNA-binding protein CIRP/hnRNP A18 regulates telomerase activity in a temperature-dependent manner.
Cold-inducible RNA-binding protein CIRP/hnRNP A18 regulates telomerase activity in a temperature-dependent manner.
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冷诱导RNA结合蛋白CIRP/hnRNP A18以温度依赖性方式调节端粒酶活性
DOI：
10.1093/nar/gkv1465
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发表时间：
2016-01-29
影响因子：
14.9
通讯作者：
Songyang Z
中科院分区：
文献类型：
--
作者：
Zhang Y;Wu Y;Mao P;Li F;Han X;Zhang Y;Jiang S;Chen Y;Huang J;Liu D;Zhao Y;Ma W;Songyang Z
端粒酶负责将端粒重复序列添加到染色体末端，由逆转录酶TERT和RNA亚基TERC组成。端粒酶的表达和活性受到严格调控，在85%的人类癌症中发现了端粒酶的异常激活。为了更好地了解端粒酶的调控，我们采用免疫沉淀结合质谱（IP-MS）技术鉴定了冷诱导rna结合蛋白（CIRP或hnRNP A18）作为端粒酶的相互作用因子。我们发现CIRP是维持端粒酶在32°C和37°C下活性所必需的。此外，通过CRISPR-Cas9或siRNA敲低抑制CIRP导致端粒酶活性降低和端粒长度缩短，表明CIRP在端粒维持中发挥重要作用。我们在这里也提供了证据，表明CIRP通过直接结合TERC与活性端粒酶复合物相关联，并调节端粒酶的Cajal体定位。此外，CIRP还调节TERT mrna的水平。在较低的温度下，TERT mRNA以依赖cirp的方式上调，以补偿端粒酶活性的降低。综上所述，这些发现强调了CIRP在调节TERT和TERC中的双重作用，并揭示了一类新的端粒酶调节剂在低温条件下的反应。
The telomerase is responsible for adding telomeric repeats to chromosomal ends and consists of the reverse transcriptase TERT and the RNA subunit TERC. The expression and activity of the telomerase are tightly regulated, and aberrant activation of the telomerase has been observed in >85% of human cancers. To better understand telomerase regulation, we performed immunoprecipitations coupled with mass spectrometry (IP-MS) and identified cold inducible RNA-binding protein (CIRP or hnRNP A18) as a telomerase-interacting factor. We have found that CIRP is necessary to maintain telomerase activities at both 32°C and 37°C. Furthermore, inhibition of CIRP by CRISPR-Cas9 or siRNA knockdown led to reduced telomerase activities and shortened telomere length, suggesting an important role of CIRP in telomere maintenance. We also provide evidence here that CIRP associates with the active telomerase complex through direct binding of TERC and regulates Cajal body localization of the telomerase. In addition, CIRP regulates the level of TERT mRNAs. At the lower temperature, TERT mRNA is upregulated in a CIRP-dependent manner to compensate for reduced telomerase activities. Taken together, these findings highlight the dual roles that CIRP plays in regulating TERT and TERC, and reveal a new class of telomerase modulators in response to hypothermia conditions.