One newly synthesized strand is produced continuously (the “leading” strand), whereas the opposing (“lagging”) strand is replicated in short discontinuous segments of DNA called Okazaki fragments ( Fig. As the replisome-a complex DNA replication machinery composed of multiple polymerases-moves along the chromosome, each strand is copied by one or more polymerases dedicated to that strand. The “end replication problem,” as it came to be known, stems from the inherent asymmetry of how linear duplex DNA is copied during each cell division ( Okazaki et al. With a new appreciation of the complexities of this process, it became apparent that replication of linear chromosomes presents a particular dilemma ( Watson 1972 Olovnikov 1973). The susceptibility of chromosome ends to sequence loss was recognized even before the discovery of telomerase, as the mechanisms that govern semiconservative DNA replication were elucidated. Thus, insights about the events that contribute to telomere erosion in the absence of telomerase should have great relevance to a fundamental aspect of human aging. Tissue renewal is critical to organ maintenance and regeneration telomere length reservoirs that are too short to sustain organ function throughout a normal life span can be a substantial contributing factor to age-dependent degenerative organ failure in the lung, liver, or bone marrow ( Armanios 2009). Although the cellular response to severe telomere attrition may provide an important barrier to the development of cancer ( de Lange and DePinho 1999), there is a substantial downside. Telomeres that are too short are no longer afforded the protection of the shelterin complex, with the ensuing DNA damage response leading to either cell death through apoptosis or a halt to cell division referred to as cellular senescence. In most tissues, telomerase is down-regulated, resulting in slow erosion of chromosomal termini with each round of cell division. However, telomeres only enjoy the benefits of telomerase-mediated elongation in human cells that rely on continuous proliferation, such as those found in stem cell compartments ( Artandi and DePinho 2010). This single-strand extension is also the substrate for telomerase, which replenishes chromosome ends by synthesizing additional telomeric repeats ( Collins 2011). Thus, cells make a substantial investment in both maintaining and shielding the last several hundred nucleotides of every chromosome end ( de Lange 2009). When telomeres are unprotected-for example, in response to experimental depletion of components of the shelterin complex-the loss of this critical G-rich overhang and the resulting end-to-end fusions can be catastrophic for genome stability. Protruding from the duplex DNA is a G-rich single-stranded extension ( Henderson and Blackburn 1989 McElligott and Wellinger 1997) that is also bound by ssDNA-binding subunits of shelterin.
Thousands of repeats of a 6-base-pair (bp) sequence (5′-TTAGGG-3′ on the so-called G-rich strand) comprise the duplex region of human telomeres, which provides a specialized landing pad for shelterin. In human cells, this complex task is achieved by a suite of proteins aptly titled the shelterin complex ( de Lange 2005). These natural chromosome termini must accomplish a crucial task in every cell cycle, which is to convince the exquisitely sensitive DNA repair machinery to leave these particular DNA ends alone.
Then select Task Manager.Telomeres occupy a small but very intense piece of chromosomal real estate. If you’re not sure what’s running in the background, open Task Manager by pressing the keys Ctrl+Alt+Delete at the same time. You can always reopen them when you need them. Google Chrome is known to be a big resource hog, so try closing it if you’re experiencing lag.Ĭlose anything you aren’t using at the moment, such as Spotify, Skype, or Discord. These programs can use up system resources and make it difficult for your game to run smoothly. One of the most common causes of lag is other programs running in the background. RELATED: Internet Connection Not Working? 10 Troubleshooting Tips Close Programs Running in the Background This will reset your internet connection and hopefully fix any network problems you were facing. If that didn’t work, try unplugging your router for at least 15 seconds and then plug it back in. Get in the habit of restarting your computer at least once or twice a week. All of these are necessary to keep your computer running smoothly.
A reboot of your computer allows your operating system to complete important updates, delete temporary files, clean up open files, and clear up memory.
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