The differential spatiotemporal expression pattern of shelterin genes throughout lifespan

Abstract

AGING INTRODUCTIONTelomeres are specialized chromatin structures, which cap chromosome ends and provide chromosome stability. The maintenance of telomeres requires accurate protections against DNA damage response (DDR) that would otherwise permanently stop cell division by checkpoint activation [ataxia telangiectasia mutated (ATM), and ATM-and Rad3-related (ATR) signaling] and lead to end-to-end chromosomal fusions by non-homologous end joining (NHEJ). Another threat to genome integrity stems from the inability of the conventional replication machinery to fully replicate the extremities of parental DNA, erosion compensated for by telomerase or recombination mechanisms [1,2]. To achieve chromosome end protection, telomeres are composed of repetitive DNA sequences that can fold into a terminal loop (t-loop), nucleosomes, the noncoding telomeric repeat-containing RNA (TERRA), the protein complex shelterin, and an ill-defined network of nuclear factors [3]. Shelterin is essential for telomere protection and is composed of six subunits: three bind specifically to telomeric DNA (TRF1, TRF2, and POT1) and three establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1 and TRF2, and ABSTRACTShelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in maintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends. Evidences suggest that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined. Together, this work shows that the shelterin subunits exhibit distinct spatiotemporal expression patterns, suggesting important tissue-specific functions during development and aging.

Human RAP 1 specifically protects telomeres of senescent cells from DNA damage

“…We defined a cellular culture as senescent when the number of cells did not increase for at least 4 weeks, SA‐β‐galactosidase (SA‐β‐Gal) activity was detected, and EdU incorporation accounted for < 1% of cells. As expected from replicative senescent cells and aging animal models, the levels of TRF2 greatly decreased (around 80%) in senescent cells . However, the levels of RAP1 barely changed with a mild decrease of only 15% as seen previously .…”

Mitochondrial function in skeletal myofibers is controlled by a TRF2‐SIRT3 axis over lifetime

“…Whether telomere shortening concomitant to TRF2 downregulation in skeletal muscle destabilizes the telomere‐ SIRT3 loop, as observed for other loci (Kim et al, ; Robin, Ludlow, et al, ; Robin et al, ), is an interesting hypothesis. Further, if telomere shortens in human tissues, including skeletal muscle (Daniali et al, ), diminution of TRF2, as already reported through lifetime in animal models (e.g., mice, zebrafish; Wagner et al, ), remains to be established in other human tissues. Noteworthy, recent studies focusing on another postmitotic tissue (e.g., heart) also link telomere length and TRF2 level to metabolic changes (Chang et al, , ; Oh et al, ).…”

Specific telomere protection ensured by FOXO3a upon genotoxic stress and during aging

“…It consists of proteins directly bound to telomeric DNA (in humans, TRF1, TRF2, and POT1) and other proteins that create a bridge between the duplex DNA and the 3′ overhang (in humans, TPP1/ACD and TIN2) or are simply bound to other subunits (in humans, RAP1 bound to TRF2). Among shelterin subunits, TRF2 may mediate important regulatory functions during aging, as it interconnects various aging hallmarks (genome stability, senescence, mitochondria, and immunity), is downregulated during aging in multiple tissues (Robin et al, 2020;Wagner et al, 2017), and plays pivotal roles in aging in model organisms (Kishi et al, 2008;Alder et al, 2015;Morgan et al, 2019). The multiple roles of TRF2 rely on its capacity to blunt the DNA damage response (DDR) ataxia-telangiectasia mutated (ATM) checkpoint and non-homologous DNA repair at chromosomal termini, in addition to genomewide transcriptional functions (Ye et al, 2014).…”