Essential Roles for Polymerase Theta-Mediated End Joining in Repair of Chromosome Breaks

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  • March 20, 2019
Creator
  • Wyatt, David
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • DNA double strand breaks (DSBs) constitute a rare but lethal class of genomic damage that must be efficiently repaired. Deficiencies in DSB repair pathways manifest themselves as severe phenotypes including cancer predisposition, accelerated aging, and immunodeficiency. On the cellular level, failure to repair DSBs can result in genomic abnormalities, chromosomal rearrangements, and apoptosis. In mammalian cells, repair of DSBs proceeds by classical nonhomologous end joining (NHEJ), homologous recombination (HR), or by a third loosely described non-canonical repair pathway, termed alternative end joining (Alt-EJ). Amongst the most clearly defined characteristics of Alt-EJ is the presence microhomology, or small patches of complementary DNA sequence flanking a chromosome break, in the repair junction. DNA Polymerase Theta has been implicated as a primary mediator of this alternative repair pathway, but its cellular mechanism and role relative to canonical repair pathways is poorly understood. We show that Polymerase Theta-mediated end joining (TMEJ) accounts for most repair associated with microhomologies, and is made efficient by coupling a microhomology search to removal of nonhomologous tails and microhomology-primed synthesis across broken ends. In contrast to NHEJ, TMEJ efficiently repairs end structures expected after aborted homology-directed repair (5’ to 3’ resected ends) or replication fork collapse. It typically does not compete with canonical repair pathways, but in NHEJ-deficient cells is engaged more frequently and protects against translocation. Cell viability is also severely impaired upon combined deficiency in Polymerase Theta and a factor that antagonizes end resection (Ku or 53BP1). TMEJ thus employs a flexible mechanism to help sustain cell viability and genome stability by rescuing chromosome break repair when resection is misregulated or NHEJ is compromised.
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  • In Copyright
Advisor
  • Ramsden, Dale
  • Ahmed, Shawn
  • Vaziri, Cyrus
  • Sekelsky, Jeff
  • Emanuele, Michael
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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