Difference between revisions of "CH391L/S2013 Alesha Stewart Apr 17 2013"
(New page: "p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression" Authors: H Zheng, L Chen, W J Pledger, J Fang, and J Chen ==Background & Introduction== The TP53...)
Revision as of 17:28, 15 April 2013
"p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression"
Authors: H Zheng, L Chen, W J Pledger, J Fang, and J Chen
Background & Introduction
The TP53 gene encodes for the tumor suppressor protein, protein 53 (p53). p53 is a transcription factor and can turn on genes to carry out particular functions. It serves as a regulator of the cell cycle to maintain genome integrity . Assaults to the DNA can lead to DNA stress that result in the accumulation and activation of p53 in the nucleus. The p53 response varies with the nature of the cell and stress. The protein can initiate cell cycle arrest, apoptosis, or DNA repair in attempt to help the cell recover . Cells without functional p53 do not respond properly to damage, and this makes them vulnerable to tumorigenesis. In p53-null mouse embryonic fibroblast it was observed that the cells developed abnormal chromosomal characteristics due to faulty segregation. Similar trends were also seen in other types of p53-null cells indicating the importance of the protein in maintaining genome integrity. p53 is believed to play a role in multiple repair pathways by either direct or indirect involvement .
Several mutations can build up; and because of this, in 1994 it was reported that mutations in the p53 gene were present in over 50% of human cancers. These mutations were widespread and found in 50 different types of cells and tissues, with most of them occurring in the DNA-binding domain of p53 . Although mutations are often associated with negative outcomes, some p53 mutations have lead to DNA damage resistance. With this, it is apparent that p53 impacts the response to DNA damage in contradicting and complex manners .
Ionizing radiation (IR) requires Ataxia telangiectasia mutated (ATM), a protein kinase involved in double-strand breaks (DSB), to induce p53. DSBs are repaired in slow (up to 24 hours) and fast (2- 6 hours) phases. Approximately 80% of breaks are repaired during the fast phase. ATM signaling functions in the slow phase to repair DSBs located in constitutive heterochromatin (HC). These regions of the genome are highly compact and repetitive, and form centromeres or telomeres . Damage from IR occurs at the same rate in HC and euchromatin, but there is a reduced amount and clearing rate of γH2AX foci at the site in HC. The histone variant H2AX is phosphorylated in the event of DNA damage, thus γH2AX foci formation indicate that DSBs are present . Since HC is wound so tightly, access to the DNA is limited and DSB repair is delayed. The chromatin must be remodeled to grant the repair factors a path to the DNA, thus ATM phosphorylates KAP1 (a transcription activator) to initiate relaxation of HC .
After DNA is replicated biochemical marks need to be made and recognized for HC packaging. Hypoacetylation and methylation are used to characterize HC and initiate the transition between euchromatin and HC . Histone H3 methylated at lysine 9 trimethylation (H3K9me3) represses transcription and silences genes after DNA damage. In mouse cells, the histone methyltransferase SUV39H1/2 regulates H3K9me3 and telomere modification to protect HC and DSB repair. However, the Jumonji domain 2 family demethylase (JMJD2b) reverses methylation done by H3K9me3 and negates the effectiveness of SUV39H1. Therefore, overexpression of JMJD2b has been linked to cancer development and chromosome instability. This research investigates how p53 affects the events of DNA damage repair via regulation of JMJD2b and SUV39H1 levels .
HCT116: colon carcinoma, p53 wild type
A549: lung adenocarcinoma, p53 wild type
U2OS: osteosarcoma, p53 wild type
U2OS-E6: U2OS stably transfected with retrovirus vector expressing HPV E6
H1299: non-small cell lung carcinoma, p53 null