Abstract
ABSTRACT Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice.
Highlights
DNA damage can be induced by numerous internal and external sources, such as the collapse of DNA replication forks and exposure to exogenous highenergy radiation [1]
Leucine zipper and ICAT domain containing (LZIC) is a putative member of the WNT signaling pathway, which typically regulates the activity of TCF/LEF family transcription factors and has been implicated in response to ionizing radiation (IR) [22]
Differential expression was determined by comparing whole genome expression profiling 24 h following 5 Gy of IR with cells which were left untreated for both LZIC KO and the CRISPR control (Figure 1A)
Summary
DNA damage can be induced by numerous internal and external sources, such as the collapse of DNA replication forks and exposure to exogenous highenergy radiation [1]. In addition to DNA break repair pathways, the DDR includes a series of specialized DNA damage sensing and signaling proteins which arrest the cell at specific checkpoints during the cell cycle [3]. These checkpoints allow for the completion of DNA repair prior to DNA replication and cell division [4]. Most widely studied is the loss of p53 and p21 proteins resulting in failure to activate G1 checkpoint [7,8]. The G2/M checkpoint becomes critically important for the maintenance of cell genome stability [9]
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