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Germline genome stability is regulated by the chromatin remodeler SMARCAD1 in C. elegans

Veroli, Maria Victoria (2023) Germline genome stability is regulated by the chromatin remodeler SMARCAD1 in C. elegans. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The reproductive success of a specie is critically influenced by its ability to protect the genetic information that will be transmitted across generations. As a consequence, it is not surprising the low tolerance germ cells have to the defective function of key genes involved in zygotic development. Among those genes are those directly involved in the maintenance of germline genome stability, that guard the genome from endogenous and exogenous insults through their involvement in DNA repair mechanisms. Consequently, due to this tight link between reproduction and DNA damage repair, the effects on fertility can be used as a readout of defects in the DNA repair machinery. One of those proteins is the chromatin remodeler SMARCAD1, which is involved in the homologous recombination pathway and has been involved in mice fertility. So far, an integrated understanding of SMARCAD1 functions remained to be addressed because of the lack of a suitable whole organism model in which to perform the studies. Here, we introduce a new player that will aid studies that allow the link of specific cellular functions with their effect on reproduction and development, the nematode Caenorhabditis elegans. We hypothesize that C. elegans SMARCAD1 ortholog promotes fertility by aiding in the maintenance of germline genome stability. Through the creation of the null allele of SMARCAD1 ortholog, smrd-1, we show that its function in HR is conserved and test that this function contributes to its role in genome stability. We also present for the first time studies on smrd-1 function in meiosis, showing loss of smrd-1 elicits a differential response to DNA damage in meiotic versus mitotic nuclei. Based on phenotypical and experimental results, we show that smrd-1 does not confer a mutator phenotype and that the decrease in fertility of this mutant may be associated with changes in epigenetic modifications. Overall, this work provides a new model that expands the understanding of smrd-1 functions which encompasses its effect on reproduction.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Veroli, Maria Victoriaviv26@pitt.eduviv26
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorYanowitz, Judith L.yanowitzjl@mwri.magee.edu
Committee ChairGhazi, Arjumandarjumand.ghazi@chp.edu
Committee MemberVan Houten, Bennettvanhoutenb@upmc.edu
Committee MemberBerman, Andrea J.AJB190@pitt.edu
Committee MemberOrwig, Kyle E.orwigke@upmc.edu
Date: 24 March 2023
Date Type: Publication
Defense Date: 12 July 2022
Approval Date: 24 March 2023
Submission Date: 17 August 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 147
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: C. elegan, smrd-1, SMARCAD1, genome instability, DNA damage, transgenerational
Date Deposited: 24 Mar 2023 15:38
Last Modified: 24 Mar 2023 15:38
URI: http://d-scholarship.pitt.edu/id/eprint/43634

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