Abstract
Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, overexpression of the MYC transcription factor increases the phosphorylation of serine 139 in histone H2AX (member X of the core histone H2A family), which forms so-called γH2AX, the most widely recognized surrogate biomarker of double-stranded DNA breaks (DSBs). Paradoxically, oncogenic MYC can also promote the resistance of cancer cells to chemotherapeutic DNA-damaging agents such as cisplatin, clearly implying an antagonistic role of MYC in genomic instability. In this review, we summarize the underlying mechanisms of the conflicting functions of MYC in genomic instability and discuss when and how the oncoprotein exerts the contradictory roles in induction of DSBs and protection of cancer-cell genomes.
Highlights
MYC as a Transcription FactorThe MYC family of transcription factors directly and indirectly regulates various genes involved in cell proliferation [1], cellular metabolism [2], induction of apoptosis [3], blocking of differentiation [4], and initiation and promotion of cancer [5,6,7]
It is important that MYC has been identified as one of the “Yamanaka” factors, along with three other distinct transcription factors, SOX2, OCT4, and KLF4, which are all essential for the establishment of inducible pluripotent stem cells by reprograming transcriptional networks of fully differentiated somatic cells [43,44,45]
Given that rapidly proliferating cancer cells, which naturally produce oncogenic MYC, accumulate more genomic instability, it is logical to assume that late-stage or recurrent cancer cells, which are expected to carry high levels of MYC, must have accumulated more DNA damage
Summary
The MYC family of transcription factors directly and indirectly regulates various genes involved in cell proliferation [1], cellular metabolism [2], induction of apoptosis [3], blocking of differentiation [4], and initiation and promotion of cancer [5,6,7]. L-MYC expression is evident in both neonatal and adult lung tissues and most frequently overexpressed in lung cancer, including small-cell lung carcinomas [9], suggesting a non-redundant biology sustained by each member of the MYC family of transcription factors. MYC–MAX heterodimer formation is crucial for MYC-dependent gene transcription, cell proliferation, apoptosis, and oncogenic transformation [23,24], but MYC may function as a transcription factor in a MAX-independent manner [25,26,27,28], implying the presence of a non-MAX heterodimeric binding partner of MYC to recognize the E-box. In addition to a new emerging research area regarding the transcription-independent function of MYC, in protein translation and DNA replication [34], it is important to identify downstream effectors of MYC-dependent gene transcription to better understand the multiple roles of MYC in various cell behaviors, such as cell proliferation survival, apoptosis, genomic instability, and cancer
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