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HCINAP regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

ABSTRACT: Through RNA-seq of wildtype and hCINAP-deleted U2OS cells and whole genome bisulfite sequencing of the two U2OS cells, we show here that hCINAP is responsible for genomic stability and DNA damage response. Deletion of hCINAP directly decreased genomic stability and caused drug sensitivity. Also, when hCINAP is deleted, many genes are upregulated. These genes are involved in aging, DNA damage response and leukemia. In our wet lab experiment results, knockdown of hCINAP sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA damage response and its role in AML resistance to therapy. RNA-seq analysis was performed by ANNOROAD. Briefly, the total RNA from wild-type and knockout hCINAP U2OS cells was extracted, and sequences were performed with Illumina Solexa Ultrasequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134342 | GEO | 2019/07/22

REPOSITORIES: GEO

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Project description:Barr2017 - Dynamics of p21 in hTert-RPE1 cells This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage This model is described in the article: DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C. Nat Commun 2017 Mar; 8: 14728 Abstract: Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. This model is hosted on BioModels Database and identified by: BIOMD0000000660. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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HCINAP regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

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