http___www.irb.hr_Izdvojeno_Ruderovac-koautor-rada-objavljenog-u-casopisu-Nature_1.xml
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The scientists analysed 17 million ‘single nucleotide variants’ – mutations in just one nucleotide (letter) of the DNA sequence – by examining 650 human tumours from different tissues. These were ‘somatic’ mutations, meaning they are not inherited from parents or passed down to children, but accumulate in our bodies as we age. Such somatic mutations are the main cause of cancer. Many result from mutagens, such as tobacco smoke or ultraviolet radiation, and others come from naturally occurring mistakes in copying DNA as our tissues renew. Ben Lehner and his team had previously described that somatic mutations are much more likely in some parts of the human genome, thus damaging genes that may cause cancer. In a new paper published on 23rd February in Nature, they show that this is because genetic mistakes are better repaired in some parts of the genome than in others. This variation was generated by a particular DNA repair mechanism called “mismatch repair” – a sort of a spellchecker that helps fix the errors in the genome after copying. Lehner and Supek show that the efficiency of this ‘DNA spellchecker’ varies depending on the region of the genome, with some parts of chromosomes getting more attention than others. Turning the tables of mutation rates The work presented by Lehner and Supek sheds new light on a process that was unexplored – what makes some parts of the human genome more vulnerable to damage? “We found that regions with genes switched on had lower mutation rates. This is not because less mistakes are happening in these regions but because the mechanism to repair them is more efficient”, explains Ben Lehner, group leader, ICREA and AXA professor of risk prediction in age-related diseases at the EMBL-CRG Systems Biology unit in Barcelona. The ‘mismatch repair’ cellular machinery is extremely accurate when copying important regions containing genes that are key for cell functioning, but becomes more relaxed when copying less important parts. In other words, there appears to be a limited capacity for DNA repair in our cells, which is directed where it matters most. The CRG researchers also found that the rate of mutation differs for around 10% of the human genome in cells originating from different tissues. In particular, liver, colorectal and lymphocyte malignancies present more mutations in some parts of our chromosomes, while breast, ovarian and lung cancers accumulate more mutations in other places. They found that genes that are important and switched on (expressed) in a particular tissue also exhibit less mutations in tumours of that tissue; the effect extends into the surrounding DNA. But what gives the important genes a higher resilience to damage? “The difference is not in the number of new mutations but in the mechanism that keeps these mutations under control”, comments Fran Supek, CRG postdoctoral researcher and first author of the paper. “By studying cancer cells, we now know more about maintaining DNA integrity, which is really important for healthy cells as well”, he adds. Once the ‘genomic spellchecker’ has been disabled in a cell, the scientists observed that genetic information started decaying not only very rapidly, but also equally in all parts of the genome - neither the important nor the less important parts can were repaired well anymore. DNA mismatch repair is known to be switched off in some tumours from the colon, stomach and uterus, producing ‘hypermutator’ cancer in those organs. The accumulation of harmful changes in DNA is a normal process occurring in all human cells every time they divide. Therefore this research not only makes an important contribution not only to cancer research, but also may lead to insights into aging and genetic diseases as well.
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Somatske mutacije nisu naslijeđene od naših roditelja već se akumuliraju u tijelu kako starimo, a glavni su okidač raka. Velik broj somatskih mutacija nastaje kao rezultat djelovanja mutagena, poput dima duhana ili ultraljubičastog zračenja, dok se drugi dio odnosi na greške nastale prirodnim putem tijekom kopiranja DNK dok se naša tkiva obnavljaju. Otprije je poznato da su takve somatske mutacije mnogo vjerojatnije u određenim dijelovima ljudskog genoma, a ova studija otkriva da se to događa jer se genetske greške ne popravljaju ravnomjerno u čitavom genomu. Autorski dvojac Lehner i Supek, koji u Barceloni dovršava svoj postdoktorat, pokazali su da efikasnost 'provjere pravopisa' u DNA varira ovisno o području genoma, što baca novo svjetlo na dosad neistraženo pitanje uzroka veće ranjivosti određenih dijelova ljudskog genoma. 'Područja genoma s eksprimiranim genima imaju manje mutacija. To nije zato što se pojavljuje manje pogrešaka, već zato što je mehanizam njihova popravka mnogo efikasniji.'– pojasnio je dr. Lehner. Tzv. 'mismatch repair' popravak je izuzetno precizan kada kopira dijelove koji sadrže gene važne za funkcioniranje stanice, dok pri kopiranju manje važnih dijelova preciznost opada. Drugim riječima, kapacitet za popravak DNK u našim stanicama je limitiran, ali je i usmjeren je tamo gdje je najpotrebniji. Također, ova studija je pokazala da se brzina oštećivanja raznih dijelova genoma mijenja ovisno o vrsti tumora. Primjerice, rak jetre, crijeva ili limfom imaju više mutacija u određenim područjima, dok rak dojke, jajnika i pluća akumulira više mutacija na drugim mjestima. Geni koji su 'uključeni' (eksprimirani) u nekom tkivu imaju manje mutacija, a zaštitni efekt 'provjere pravopisa' se proteže i u okolnu DNA takvih važnih gena. 'Proučavajući stanice raka, naučili smo nešto novo o održavanju cjelovitosti genoma, što je iznimno važno i za zdrave stanice', dodao je dr. Supek. Jednom kad se 'provjera pravopisa' isključi u stanici, genetska informacija počinje degradirati vrlo brzo, i k tome podjednako u svim dijelovima genoma: niti bitni, niti nebitni dijelovi ne mogu se popravljati. Ovo događa u nekim slučajevima raka debelog crijeva, maternice ili želuca, stvarajući 'hipermutirajuće' tumore u tim organima. Akumulacija štetnih promjena u DNK je normalan proces koji se događa u svim ljudskim stanicama svaki puta kada se one dijele. Zbog toga ovo istraživanje daje važan doprinos ne samo istraživanju raka, već otvara put daljnjim saznanjima i otkrićima u području ljudskog starenja i genetskih bolesti općenito.