**2.3. The duplicated GGAA-motifs in the 5′-upstream regions of the human DNA repair factor-encoding genes**

The duplicated GGAA (TTCC) motif is present adjacent to the TSS of the human *TP53* gene [34], the expression of which is regulated by IFN-α and β [35]. IRF1 was reported to be a negative regulator of the human *TERT* promoter in response to IFN-γ [36]. In addition, IRF-5 has been shown to upregulate the expression of DNA repair/apoptosis-associated genes [37]. Moreover, DNA damage initiates an immune response that regulates DNA repair-associated genes [38]. These observations suggest that the immune responses and DNA damage responses might be co-dependent, and that the duplicated GGAA-motifs have important roles in controlling the expression of genes that encode DNA repair-associated factors in response to IFN-induced signals.

It should be noted that the duplicated GGAA-motif is present in the promoter regions of the human *Poly(ADP-ribose) polymerase 1*(*PARP1*) [39, 40] and *XRCC1* [41] genes. The duplicated GGAA-motifs are present near the TSS of the *ADPRHL2* (*ARH3*) and the *ZC3HAV1* genes, which encode mitochondria-localizing poly(ADP-ribose) (PAR) degrading enzyme [42] and an anti-viral RNA-binding protein PARP13 [43, 44], respectively. These findings suggest that the expression of genes encoding single-strand DNA break repair factors is commonly regulated by the duplicated GGAA-motifs.

also the *MDH2* gene (which encodes NAD+

transcription control system [76, 77].

PARP1 itself contributes to NAD+

SIRT1, which is an NAD+

NAD+

stress.

**3.1. The transcription profile may be controlled by the NAD<sup>+</sup>**

duplication of the GGAA-motif, may be regulated by the NAD+

chromatin remodeling [86]. Thus, the accumulation of NAD+

mitochondria.

**profiles**


http://dx.doi.org/10.5772/intechopen.71095

111

**/NADH balance**

/NADH ratio [82]. Notably,

/NADH

molecules or NAD+



that duplicated GGAA-dependent transcription could affect the metabolism of malate in the

A New Insight into the Development of Novel Anti-Cancer Drugs that Improve the Expression…

Recently, a study using a CAP-SELEX analysis showed that different transcription factors, such as FOXO1 and ETS family proteins, are mediated by a DNA that contains a GGAAcore motif [71]. As described above, a number of promoters or regulatory regions of human genes that encode immune response-/DNA repair-/mitochondrial function-associated proteins contain overlapping or duplicated GGAA-containing motifs. Thus, the alteration of the profile of the GGAA-motif-binding proteins or their associated protein factors may allow for the control of appropriate cellular responses against viral infection, DNA damage, and oxidative/nutrient/metabolic stress. Importantly, the DNA damage responses affect the transcriptional state [72] through oxidative stress, which is mainly produced by the mitochondria [73, 74]. NF-κB- and p53-dependent transcription, which regulates the expression of the ISGs and DNA repair factor-encoding genes, is also affected by oxidative stress [75]. Thus, metabolites that are mainly produced by respiration or mitochondrial functions may influence the

We have reported that the promoter regions of the human *TP53*, *HELB*, and telomere maintenance factor-encoding genes respond positively to Rsv [46, 48, 78]. Rsv not only activates

[80]. Importantly, low-dose Rsv activates mitochondrial complex I [81] to upregulate the

the C terminal-binding protein (CtBP) [83, 84] has a central role in this regulation as a metabolic sensor. Moreover, PARP1 poly(ADP-ribosyl)ates transcription elongation factor NELF to release the paused RNA pol II-dependent transcription [85], suggesting that

nuclear PAR can be utilized by NUDIX5 to supply ATP molecules, which are required for

ratio-sensitive proteins, including GGAA-motif binding TFs, might affect the transcription of ISGs/DNA repair/mitochondrial function-associated genes in response to metabolic

It should be noted that PARP activity is upregulated in tumors and cancer cells [44]. Because the duplicated GGAA-motifs are present in the 5′-upstream regions of the human *PARP* and *PARG* genes [40], subtle changes in the quality/quantity profile of the GGAA-binding TFs may

/NADH ratio, to induce the expression of duplicated GGAA-motif-driven genes. The transcription of the bidirectional promoter-driven *BRCA1/NBR2* genes, which contain a

**3. The possible roles of metabolic states that can alter transcription** 

The promoter activities of the human *WRN* and *TERT* genes, both encoding telomere maintenance factors, positively respond to both 2-deoxy-d-glucose (2DG) [45] and *trans*-resveratrol (Rsv) [46], which are caloric restriction (CR) mimetic drugs that have been shown to prolong the life span of several organisms [47]. The natural compound Rsv upregulates the expression of the *HELB* gene [46, 48], which encodes DNA replication and DNA double strand break repair-helicase HELB (HDHB) [49–52]. Moreover, the 5′-regulatory regions of the genes that encode DNA repair factors, such as *XPB*, *RB1*, *RTEL1*, *ATR*, *TP53*, and *CDKN1A (p21)*, contain GGAA duplications near the TSS [53]. Several of the DNA repair factors are localized in the mitochondria and may also regulate the mitochondrial functions [53].
