Project Details
Description / Abstract
Life begins when an egg and a sperm from parents merge into a single cell, the fertilised egg, which multiplies into many cells to create our body. Sperm and egg each contribute 23 chromosomes, making a total of 46 chromosomes in the fertilised egg. When our body produces sperm or eggs, cells undergo a special cell division called meiosis, which halves the number of chromosomes. Chromosomes consist of long stretches of DNA, which encode the many genes required to make our body. When meiosis occurs, the chromosomes inherited from the mother are reshuffled with those from the father, forming a completely new set of chromosomes with a unique combination of genes. This reshuffling process diversifies gene combinations from generation to generation, creating evolutionary adaptability to environmental changes.
The process of reshuffling the genes in the chromosomes is called recombination. Recombination operates by cutting DNA and exchanging sections of the DNA between maternal and paternal chromosomes. If recombination fails, the wrong number of chromosomes, or incorrectly assembled chromosomes, can be passed into sperm and eggs. This type of fault is a leading cause of miscarriage and congenital syndromes including Down, Edward, Patau (trisomy 21, 18, 13) & Turner (monosomy X). Overall, about 0.3% of newborn infants have an incorrect chromosome number. Given its importance, organisms are equipped with various mechanisms to ensure correct meiotic recombination. I am investigating how meiotic recombination is controlled. For this research I use yeast cells, which undergo meiosis just like humans, and are easy to manipulate experimentally.
When meiosis begins, cells make a group of proteins that act together as scissors to cut the DNA for recombination. To produce normal sperm and eggs, these DNA scissors need to be well controlled to prevent recombination failures, but the control mechanisms are still enigmatic. Recent findings have led me to hypothesise that proteins called Hop1 and Red1 direct the activity of these scissors, telling them where, when, and how often to cut DNA.
Hop1 and Red1 are part of the 'chromosome scaffold' of meiotic cells and are believed to help the scissors bind to chromosomes. I discovered further roles for Hop1 and Red1 in the process. Paradoxically, even though their main role is to promote the recruitment of DNA scissors to chromosomes, I found that Hop1 and Red1 can prevent scissors from randomly binding along chromosomes. Moreover Hop1 and Red1 are needed not just to recruit but also to activate the scissors for cutting DNA. Also, Hop1 and Red1 pay extra attention to short chromosomes, preferentially directing the DNA scissors to short chromosomes to ensure they get cut. Overall I propose that these two 'manager proteins' Hop1 and Red1 direct the scissors to chromosomal locations favourable for correct recombination, while simultaneously preventing the scissors from cutting at dangerous places, both by excluding them from such locations and by allowing the scissors to cut DNA only when both manager proteins are present.
This project investigates these new functions of Hop1 and Red1 to test my hypothesis. I will elucidate how these proteins behave in meiotic cells to understand the molecular mechanisms that control recombination. Since these scissors and manager proteins are present in human and yeast, new knowledge from this study will advance our understanding of how our eggs and sperm are made and how their production process can fail. This work will therefore make critical contributions to the understanding of fertility and the formation of new genomes and, to the development of reproductive medicine. For example, once the risk of chromosome abnormalities due to mutations in these manager genes is understood, it will help patients to select the best fertility treatments. Such understanding may also help design strategies to avoid faulty meiosis and consequent health problems completely.
The process of reshuffling the genes in the chromosomes is called recombination. Recombination operates by cutting DNA and exchanging sections of the DNA between maternal and paternal chromosomes. If recombination fails, the wrong number of chromosomes, or incorrectly assembled chromosomes, can be passed into sperm and eggs. This type of fault is a leading cause of miscarriage and congenital syndromes including Down, Edward, Patau (trisomy 21, 18, 13) & Turner (monosomy X). Overall, about 0.3% of newborn infants have an incorrect chromosome number. Given its importance, organisms are equipped with various mechanisms to ensure correct meiotic recombination. I am investigating how meiotic recombination is controlled. For this research I use yeast cells, which undergo meiosis just like humans, and are easy to manipulate experimentally.
When meiosis begins, cells make a group of proteins that act together as scissors to cut the DNA for recombination. To produce normal sperm and eggs, these DNA scissors need to be well controlled to prevent recombination failures, but the control mechanisms are still enigmatic. Recent findings have led me to hypothesise that proteins called Hop1 and Red1 direct the activity of these scissors, telling them where, when, and how often to cut DNA.
Hop1 and Red1 are part of the 'chromosome scaffold' of meiotic cells and are believed to help the scissors bind to chromosomes. I discovered further roles for Hop1 and Red1 in the process. Paradoxically, even though their main role is to promote the recruitment of DNA scissors to chromosomes, I found that Hop1 and Red1 can prevent scissors from randomly binding along chromosomes. Moreover Hop1 and Red1 are needed not just to recruit but also to activate the scissors for cutting DNA. Also, Hop1 and Red1 pay extra attention to short chromosomes, preferentially directing the DNA scissors to short chromosomes to ensure they get cut. Overall I propose that these two 'manager proteins' Hop1 and Red1 direct the scissors to chromosomal locations favourable for correct recombination, while simultaneously preventing the scissors from cutting at dangerous places, both by excluding them from such locations and by allowing the scissors to cut DNA only when both manager proteins are present.
This project investigates these new functions of Hop1 and Red1 to test my hypothesis. I will elucidate how these proteins behave in meiotic cells to understand the molecular mechanisms that control recombination. Since these scissors and manager proteins are present in human and yeast, new knowledge from this study will advance our understanding of how our eggs and sperm are made and how their production process can fail. This work will therefore make critical contributions to the understanding of fertility and the formation of new genomes and, to the development of reproductive medicine. For example, once the risk of chromosome abnormalities due to mutations in these manager genes is understood, it will help patients to select the best fertility treatments. Such understanding may also help design strategies to avoid faulty meiosis and consequent health problems completely.
| Status | Active |
|---|---|
| Effective start/end date | 2/10/22 → 1/10/27 |
| Links | https://gtr.ukri.org/projects?ref=MR%2FW027313%2F1 |