Comparative genomics of mortal and immortal cnidarians unveils novel keys behind rejuvenation

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# https://www.pnas.org/doi/full/10.1073/pnas.2118763119 [https://imt.cx/images/pnas.2118763119fig02.jpg|center] # Primary hallmarks (causes of damage) ## Genome instability {br} ### XRCC5 {br} XRCC5, or Ku80, is a helicase involved in DNA repair and chromatin remodelling. It has been found associated with the telomeres and with WRN. XRCC5-null mice live about 38 weeks and appear to age prematurely. As such, XRCC5 may play a role in human ageing. ([1|https://genomics.senescence.info/genes/entry.php?hgnc=XRCC5]) ### RAD51C {br} It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. ([1|https://pubmed.ncbi.nlm.nih.gov/29158291/]) ### LMNA {br} Hutchinson-Gilford's progeroid syndrome, caused by a mutation in LMNA, is characterized by features resembling accelerated ageing. ([1|https://genomics.senescence.info/genes/entry.php?hgnc=LMNA]) ### POLA2 {br} We found that loss of POLA2 leads to an increase in spontaneous double strand breaks DSB formation. Loss of POLA2 also slows DSB repair kinetics after treatment with etoposide and inhibits both of the major double strand break repair pathways: non-homologous end-joining and homologous recombination. ([1|https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352189/]) ### TOP3B {br} TOP3B affects the supercoiling of the DNA. Mice lacking TOP3B develop normally but have a shorter lifespan. ([1|https://genomics.senescence.info/genes/entry.php?hgnc=TOP3B]) ### MSH2 {br} DNA mismatch repair protein Msh2, MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair. ([1|https://en.wikipedia.org/wiki/MSH2]) ### POLD1 {br} The gene polymerase delta 1 (POLD1) encodes the large, POLD1/p125, catalytic subunit of the DNA polymerase delta (Polδ) complex. The Polδ enzyme is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand. The POLD1/p125 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage. ([1|https://en.wikipedia.org/wiki/POLD1]) ### RFC3 {br} Our data indicate RFC3 mutation and loss of RFC3 expression occur in large fractions of GC and CRC and suggest that these alterations may contribute to the cancer pathogenesis by deregulating DNA repair and replication. ([1|https://pubmed.ncbi.nlm.nih.gov/20573375/]) ### GEN1 {br} The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. ([1|https://pubmed.ncbi.nlm.nih.gov/20573375/]) ## Telomere shortening {br} ### GAR1 {br} Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme. ([1|https://pubmed.ncbi.nlm.nih.gov/20573375/]) ### POT1 {br} This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=POT1]) ## Epigenetic alterations {br} ### MORC3 {br} Nuclear matrix protein which forms MORC3-NBs (nuclear bodies) via an ATP-dependent mechanism and plays a role in innate immunity by restricting different viruses through modulation of the IFN response. Mechanistically, possesses a primary antiviral function through a MORC3-regulated element that activates IFNB1, and this function is guarded by a secondary IFN-repressing function. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=MORC3]) ## Loss of proteostasis {br} ### TPP1 {br} High expression of TPP1 is found in bone marrow, placenta, lung, pineal and lymphocytes. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates and has weaker endopeptidase activity. It is synthesized as a catalytically inactive enzyme which is activated and autoproteolyzed upon acidification. ([1|https://en.wikipedia.org/wiki/Tripeptidyl_peptidase_I]) # Antagonistic hallmarks (responses to damage) ## Deregulated nutrient sensing ### None specified {br} ## Mitochondrial dysfunction {br} ### TXN {br} The protein encoded by this gene acts as a homodimer and is involved in many redox reactions. The encoded protein is active in the reversible S-nitrosylation of cysteines in certain proteins, which is part of the response to intracellular nitric oxide. This protein is found in the cytoplasm. Two transcript variants encoding different isoforms have been found for this gene. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=TXN]) ### GSR {br} This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. This enzyme is a homodimeric flavoprotein. It is a central enzyme of cellular antioxidant defense, and reduces oxidized glutathione disulfide (GSSG) to the sulfhydryl form GSH, which is an important cellular antioxidant. Rare mutations in this gene result in hereditary glutathione reductase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been found. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=gsr]) ## Cellular senescence {br} ### SPICE1 {br} Involved in metaphase plate congression; mitotic spindle assembly; and regulation of centriole replication. Located in centriole; centrosome; and spindle. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPICE1]) ### HECW2 {br} This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=HECW2]) ### MAU2 {br} MAU2 (MAU2 Sister Chromatid Cohesion Factor) is a Protein Coding gene. Diseases associated with MAU2 include Cornelia De Lange Syndrome and Tongue Carcinoma. Among its related pathways are Cell Cycle, Mitotic and Cohesin complex - Cornelia de Lange syndrome. Gene Ontology (GO) annotations related to this gene include protein N-terminus binding. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAU2]) ### RACGAP1 {br} This gene encodes a GTPase-activating protein (GAP) that is a compoment of the centralspindlin complex. This protein binds activated forms of Rho GTPases and stimulates GTP hydrolysis, which results in negative regulation of Rho-mediated signals. This protein plays a regulatory role in cytokinesis, cell growth, and differentiation. Alternatively spliced transcript variants have been found for this gene. There is a pseudogene for this gene on chromosome 12. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=RACGAP1]) ### ATM {br} The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATM]) # Integrative hallmarks (culprits of the phenotype) ## Stem cell exhaustion {br} ### GLI3 {br} Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=gli3]) ## Altered intercellular communication {br} ### PSEN1 {br} Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=PSEN1]) ### BMP7 {br} This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone, kidney and brown adipose tissue development. Additionally, this protein induces ectopic bone formation and may promote fracture healing in human patients. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=BMP7]) ### CLASP1 {br} CLASPs, such as CLASP1, are nonmotor microtubule-associated proteins that interact with CLIPs (e.g., CLIP170; MIM 179838). CLASP1 is involved in the regulation of microtubule dynamics at the kinetochore and throughout the spindle (Maiato et al., 2003 [PubMed 12837247]). ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=CLASP1]) ### SPAST {br} This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPAST]) ### TUBG1 {br} This gene encodes a member of the tubulin superfamily. The encoded protein localizes to the centrosome where it binds to microtubules as part of a complex referred to as the gamma-tubulin ring complex. The protein mediates microtubule nucleation and is required for microtubule formation and progression of the cell cycle. A pseudogene of this gene is found on chromosome 7. ([1|https://www.genecards.org/cgi-bin/carddisp.pl?gene=TUBG1])
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