Characterization of the novel IK complex and its role in the DNA damage response
- Defects in a plethora of cellular processes can lead to genomic instability in the cells, corresponding to activation of the DNA damage response (DDR). The scope of the diversity of these cellular processes is only beginning to be understood. We found that down-regulation of IK, inhibitor of K562, leads to activation of the DNA damage response and defects in gene expression. Previous works in B cells showed that the overexpression of IK abrogates the gamma-interferon induction of major histocompatibility (MHC) class II expression, suggesting that IK is a negative regulatior of MHC class II expression. Additionally, several large-scale mass spectrometry studies identified IK in pre-mRNA processing complexes along with other transcription cofactors. Through coimmunoprecipitation and mass-spectrometry, we identified two other interactors of IK that when down-regulated also lead to activation of the DNA damage response and defects in expression of many genes. Here we characterized this novel IK complex and its role in the DNA damage response. Components of the complex colocalize with RNA polymerase II foci, in agreement with a role of the complex in regulating gene expression. Interestingly, one of the components is phosphorylated by the central regulators of the DNA damage response, ATM/ATR, in response to a wide variety of DNA damaging agents, suggesting that the function of the complex is regulated by the DNA damage response and that this complex may play an important role in the DNA damage response. Altogether, the results presented highlight the integral relationship between processes involved in gene expression and genomic stability. These processes, such as transcription and pre-mRNA metabolism, occur on chromatin and pose a threat to genomic stability. However, they are necessary for life and for the expression of the gatekeepers of the genome. Hence, these processes must be tightly regulated to preserve genome integrity while at the same time allow gene expression to occur. Future studies will provide mechanistic details of the interface between these processes and genomic stability. An understanding of this interface may help elucidate potential mechanisms employed by precancerous lesions to become overt malignant tumors and perhaps lead to identification of novel therapeutic targets for blocking tumorigenesis.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Guan, Anna Bao Zhen
|Stanford University, Department of Cancer Biology.
|Wysocka, Joanna, Ph. D
|Wysocka, Joanna, Ph. D
|Statement of responsibility
|Anna Bao Zhen Guan.
|Submitted to the Department of Cancer Biology.
|Ph.D. Stanford University 2011
- © 2011 by Anna Bao Zhen Guan
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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