br The group of genes enriched in singletons UCEC
The group of genes enriched in singletons (UCEC, SKCM and BRCA) is also of high interest. The ectopic expression and upregu-lation of olfactory receptors in melanoma (SKCM) is a potential source of malignant transformation (Gelis et al., 2017; Ranzani et al., 2017), and it will be useful to assess their role in mutagen-esis. Likewise, it will be instructive to assess the relationships be-tween HLA gene expression and mutation loads in CESC, where a role for HPV infection is well established (Brady et al., 2000). Finally, BRCA displayed enrichment in genes involved in the unfolded protein response (UPR) pathway. UPR aims at restoring protein integrity by activating chaperon-assisted protein folding in the endoplasmic reticulum (McGrath et al., 2018; Minakshi et al., 2017; Ricciardiello et al., 2018), and our data support its activa-tion and relevance in breast cancer.
5. Synopsis and perspective
We sought to computationally examine the impact of non-B DNA structure typified by G4 DNA sequences, which likely impact transcription and replication, and of transcription directly in genome instability and cancer. We found that G4 DNA-forming sequences are enriched twofold at translocation breakpoints, strengthening the view that G4 DNA structures contribute to genomic instability in cancer; many such structures are likely to originate from L1 and SVA retrotransposons and contribute to instability. Mutations in TP53 increase the chance of G4 DNA-induced translocations, possibly through defects in homologous recombination following replication fork stalling at G4 DNA. These observations point to non-B DNA as sites of increased mutation risk that are protected in normal cells by DNA damage responses, which can be defective in cancer cells. Transcriptome analyses identify two distinct branches though which alterations in gene expression may lead to an accumulation of single 1360705-96-9 substitutions in cancer:
1) activation of cell cycle/DNA repair; and 2) loss of homeostatic control of mitochondrial respiration. It will be important to deter-mine the degree and basis by which these branches are connected, such as is being elucidated for the apoptosis inducing factor (AIF), which is important for assembly of functional mitochondrial complexes and for cell death promoted by PARP1 depletion of NADH unbalanced from its removal by the gylcohydrolase PARG in response to DNA damage (Brosey et al., 2016). Induction of the cell cycle/DNA repair operates preferentially in tumors of the kidney, lung, prostate and brain/spinal cord, whereas mitochondrial dysfunction is more prevalent in tumors of the stomach, thyroid and bile ducts. Tumor-specific alterations in gene expression associated with mutation loads also include the ectopic expression of olfactory receptor genes in skin cancer, exacerbation of the ER unfolded protein response in breast cancer and altered HLA gene expression in cervical cancer. We anticipate that future efforts will elucidate the recognition and processing of G4 and other non-B DNA structures by cellular enzymes with the aim at reducing their mutagenicity. The picture emerging from the gene expres-sion/mutation correlations points to two interesting targets for research. The first is to assess the relations of the MYBL2 axis with DNA repair responses and mutagenesis. The second is to clarify how deregulation of the mitochondrial respiratory chain and its link to the TCA cycle through the SDH complex elicits mutations. Given the prevalence of cervical, skin and breast cancer, it will furthermore be important to assess the role of HLA, olfactory receptor, and chap-eron gene expression alterations in mutation loads in these malignancies.
We thank Dr. Aleem Syed and Dr. Katharina Schlacher for comments and suggestions. This work was supported by the Cancer Prevention and Research Institute of Texas grants RR140052 and RP180813 (B.A, Z.A., J.A.T.), by a Robert A. Welch Chemistry Chair (J.A.T.) and by NIH grants R35 CA220430, P01 CA092584, CA117638, and CA200231. This research used the Texas Advanced Computing Center (TACC), which is supported by National Science Foundation (NSF) grant ACI-1134872, and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant ACI-1548562.
Please cite this article as: Bacolla, A et al., Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction, Progress in Biophysics and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.03.004
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Bhattacharjee, A., Wang, Y., Diao, J., Price, C.M., 2017. Dynamic DNA binding, junc-tion recognition and G4 melting activity underlie the telomeric and genome-wide roles of human CST. Nucleic Acids Res. 45, 12311e12324. Biffi, G., Di Antonio, M., Tannahill, D., Balasubramanian, S., 2014. Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. Nat. Chem. 6, 75e80.