G-quadruplex (G4)-driven epigenomic aging

From Longevity Wiki

Nucleic acid sequences rich in guanine are capable of forming four-stranded structures called G-quadruplexes(G4), stabilized by hydrogen bonding between a tetrad of guanine bases[1] and it generally extends over the C-rich strand forming a 3′ overhang reaching approximately 50–300 nucleotides in mammals.[2] Endogenous G4 (eG4), with its unique secondary structure, is involved in a variety of important biological processes such as gene transcription, translation regulation, telomere extension, and chromatin modification. [3]

The structures of eG4s are affected by interacting proteins in vivo. During DNA replication, double-stranded (dsDNA) is unwound into single-stranded DNA (ssDNA) by helicases[4] and stabilized by ssDNA-binding proteins. During transcription, the promoter TATA box interacts with TFIIH to melt the promoter. As a kind of nucleic acid structures, eG4s will inevitably be regulated by interacting proteins. The proteins that can interact with eG4s can be divided into two types according to their functions: one is the protein that can unfold eG4s (such as G4 helicase), and the other is the protein that can bind and stabilize eG4s. These two types of proteins together regulate the dynamics of eG4s in vivo.[3]

Transcription of the C-rich telomeric strand generates a class of telomeric repeat-containing RNAs called TERRA (TElomere Repeat-containing RNA) with distinct subtelomeric sequences at their 5′ end and the same G-rich telomeric sequence at their 3′ end. These features are shared by TERRA molecules expressed by all the organisms studied to date.[5] Recent evidence indicates that aging is a condition which results in upregulation of TERRA in different cellular settings.[6][7] The G-quadruplex structure of TERRA is an important recognition element for the TRF2 shelterin subunit and physically interacts with it to bind to telomeric DNA and also with TRF1 to preserve the telomere’s structural stability.[8][9]

The formation of telomeric quadruplexes has been shown to decrease the activity of the enzyme telomerase, which is responsible for elongating telomeres.[10][11][12]

High occurrences of oxidized guanines in G4 structures due to the oxidative stress occurring under the influence of the reactive oxygen species (ROS) affects the genome stability and promotes mutagenesis, that can destabilize the stacking of guanin, senescence, and other age-related diseases.[13][14] G4s in CDS (the coding sequence, that codes for a protein) and CpG regions (that contain several CpG methylated sequences of DNA) are the least likely regions to be affected by mutations, while enhancers and intergenic G4s are prone to higher variant-induced stabilization and destabilization due to the single-nucleotide variants.[15]

Small molecules targeting G4

Small molecules targeting G-quadruplexes are also important as potent drugs for therapy of cancer and other diseases.[16][17][18][19][20][21][22][23][24][25][26][27][28]

[29] [30] [31] [32] [33] [34] [35] [36] [37] [38]

G4 may participate in non-genetic mechanisms driving aging

G4s accumulate at specific genomic loci during aging and the coefficient of variation of the G4 signal increased with cell age.[39] This G4 accumulation drives clock-like chromatin opening, since G4 formation drives aging-associated, clock like chromatin opening.[39] It was shown that delayed genome replication is a general feature of aging loci and that G4 stimulates local transcription replication interaction to delay genome replication.[39] The authors of the article also hypothesized that G4 stability might also regulate age-associated DNA hypomethylation.[39] The authors also suggest that "perturbing G4 formation might be of particular interest for modulating natural and pathological aging".[39]


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