Nonhomologous end joining (NHEJ) is the predominant repair pathway of DSBs in non- cycling mammalian cells. In this dissertation I have shown how cellular NHEJ adapts to resolve DSBs that possess end structures that lack sequence complementarity or containing nucleotide damage. These adaptations include the ability of LIG4 to act as a “translesion ligase” as well as its ability to act as a gatekeeper of the DSB ends. I proposed that LIG4’s transition from a closed to an open confirmation ability permits specific end remodelers access to the ends. My data indicate that two of the key remodelers in cellular NHEJ are the X family polymerases Pol λ and Pol µ. These polymerases are preferentially active on distinct substrates and have distinct
mechanisms for gap filling. Thus, they have largely non-overlapping roles in cells. Further, I have proposed that to minimize pol µ-mediated error, NHEJ preferentially employs the more accurate Pol λ first. My work has, therefore, demonstrated that NHEJ is able to systematically adapt to different end structures, which speaks to the incredible flexibility of this pathway.
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