Samoorganizacija mikrotubula i motornih proteina u formiranju antiparalelnih svežnjeva diobenog vretena

doctoral thesis

• Title (english): Self-organization of microtubules and motor proteins in the formation of antiparallel bundles of mitotic spindle
• Author: Ivana Ban
• Mentor: Nenad Pavin (mentor)
• Committee member: Matko Glunčić (predsjednik povjerenstva)
• Committee member: Nenad Pavin (član povjerenstva)
• Committee member: Iva Marija Tolić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Physics); Zagreb
• Defense date and country: 2023-05-02, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Physics
• Universal decimal classification (UDC): 53 - Physics

Abstract

Dioba stanica složen je proces koji počinje formiranjem diobenog vretena koje razdvaja kromosome u dvije stanice kćeri na kraju mitoze. Diobeno vreteno je mikrostroj, sazdan od mikrotubula, koji pažljivo organizira sile koje generiraju motorni proteini, a njegova se funkcionalnost oslanja na preciznosti samoorganizacije vretena. Pogreške u samoorganizaciji vretena mogu dovesti do krive podjele kromosoma (missegregacije) koja rezultira nepravilnim brojem kromosoma u stanicama kćeri. Stanje s nepravilnim brojem kromosoma naziva se aneuploidija. Aneuploidija u kombinaciji s velikom učestalosti dobitka i gubitka kromosoma može stvoriti domino efekt koji dovodi do razvoja tumorskih tkiva. U ovoj doktorskoj tezi želimo razumjeti ključne procese koji stoje iza formiranja antiparalelnih svežnjeva diobenog vretena, kao i istražiti koje su posljedice grešaka tijekom stanične diobe nakon više generacija. Kako bismo razumjeli evoluciju tumora iz zdravih stanica, razvili smo "makrokariotip model" i pokazali da perturbiran broj kromosoma u tumorskim stanicama uglavnom proizlazi zbog brže diobe stanica koje karakterizira specifična kombinacija kromosoma ili zbog kombinacije brže diobe i nepravilne stanične smrti tih stanica. Ovaj teorijski rezultat objašnjava eksperimentalno opažene kombinacije kromosoma u različitim stadijima razvoja tumora, uključujući mali broj aneuploidnih stanica u predtumorskim stadijima, kao i visoko aneuploidne stanice u tumorskom stadiju. Također istražujemo samoorganizaciju mikrotubula u antiparalelne svežnjeve i u tu svrhu razvijamo matematički model koji uključuje dinamiku mikrotubula i motornih proteina. Rješavanjem modela pokazujemo da mikrotubuli sa svakog pola traže one sa suprotnog pola izvodeći nasumično kutno kretanje. Nakon kontakta, dva mikrotubula usmjereno klize bočno jedan duž drugoga prema antiparalelnoj konfiguraciji. Uvodimo duljinu konture mikrotubula kao mjeru aktivnosti motora koji pokreću usmjerenu rotaciju mikrotubula, što otkriva da usmjerenje motora prema minus kraju dovodi mikrotubule u antiparalelnu organizaciju. Zaključno, naš teorijski pristup pridonosi boljem razumijevanju složenog procesa stanične diobe i dugoročnih posljedica njezina neispravnog funkcioniranja te na taj način povezuje dvije različite vremenske skale relevantne za pravilno funkcioniranje stanice.

Abstract (english)

Cell division is a complex process that starts with the formation of a mitotic spindle which segregates chromosomes into two daughter cells at the end of mitosis. The mitotic spindle is a microtubule based micro-machine that carefully orchestrates the forces generated by motor proteins and its functionality relies on the accuracy of spindle self-organization. Errors in spindle self-organization can lead to missegregation which produces aneuploidy, a state with irregular number of chromosomes. Aneuploidy in combination with propensity of gaining and losing chromosome with high frequency can create a domino effect which leads to the development of tumor tissues. In this thesis we aim to understand the key processes behind the formation of an antiparallel bundle of a mitotic spindle as well as explore what are the consequences of errors during cell division after multiple generations. To understand tumor evolution from healthy cells we develop a “macro-karyotype model” and show that the perturbed number of chromosomes in tumor cells arises predominantly from a faster division of cells characterized by a specific combination of chromosomes, or together with irregular cell death. This theoretical result explains experimentally observed combination of chromosomes in different stages of tumor development including a small number of aneuploid cells in pretumor stages as well as highly aneuploid cells in tumor stage. We also investigate the selforganization of microtubules into an antiparallel bundle and for that purpose develop a mathematical model that includes the dynamics of microtubules and motor proteins. By solving the model, we show that microtubules from each pole search for those from the opposite pole by performing a random angular movement. Upon contact, two microtubules slide sideways along each other in a directed manner toward the antiparallel configuration. We introduce the contour length of microtubules as a measure of the activity of motors that drives microtubule sliding, which reveals that minus-end-directed motility drives microtubules into an antiparallel organization. In conclusion, our theoretical approach contributes to a better understanding of the complex process of cell division and the long-term consequences of its malfunctioning and thereby connects two different timescales relevant for proper cell functioning.

• Keywords: dioba stanica; formiranje diobenog vretena; antiparalelni svežnjevi; sile; missegregacija kromosoma; evolucija kariotipa; aneuploidija; makrokariotip; teorijski model
• Keywords (english): cell division; spindle assembly; antiparallel microtubule bundles; forces; chromosome missegregation; karyotype evolution; aneuploidy; macro-karyotype; theoretical model
• Language: croatian
• URN:NBN: urn:nbn:hr:217:745926
• Promotion: 2023
• Project: Number: KK.01.1.1.01.0004; Title: Provedba vrhunskih istraživanja u sklopu Znanstvenog centra izvrsnosti za kvantne i kompleksne sustave te reprezentacije Liejevih algebri; Acronym: QuantiXLie; Leader: Nenad Pavin; Jurisdiction: eu; Funder: Croatian Government and European Union; Funding stream: European Regional Development Fund - the Competitiveness and Cohesion Operational Programme
• Study programme: Title: Physics; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje fizika (doktor/doktorica znanosti, područje prirodnih znanosti, polje fizika)
• Type of resource: Text
• Extent: 108 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-07-13 09:47:46