The Role of ZMYND8 in Immunoglobulin Class Switch Recombination

Author

Daniel Benjamin Rosen

Date of Award

2019

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Nussenzweig Laboratory

Abstract

Class switch Recombination (CSR) also known as Immunoglobulin (Ig) Class switching is a genomic recombination/deletion reaction that diversifies the effector component of the antibody response but preserves antigen specificity. CSR is initiated by the enzyme activation induced cytidine deaminase (AID), which produces nucleotide mismatches in actively transcribed immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3’ Regulatory Region (3’RR), a prototypical super-enhancer located at the 3’ of the Igh locus, is essential for acceptor switch region transcription, but the mechanism by which it regulates this process is not well defined. After targeting by AID, nearby mismatches in the donor switch region are processed into DNA double strand breaks (DSBs), translocated to DSBs in the acceptor switch region, and ligated through the DNA Damage Repair (DDR) pathway, non-homologous end-joining (NHEJ). Critical components of CSR are 53BP1 and its effector RIF1 because they inhibit end resection to promote NHEJ and oppose competing pathways in DDR. However, the mechanism by which RIF1 effects end-protection in CSR and binds to 53BP1 is still unknown In these studies, I identified a novel component of the RIF1 interactome, ZMYND8, a chromatin reader and transcriptional repressor that binds to RIF1 and facilitates effective CSR. Unexpectedly, ZMYND8 promotes CSR independently of RIF1. In B cells, ZMYND8 binds active promoters and super-enhancers, including the Igh enhancer the 3’RR. ZMYND8 controls 3’RR activity by regulating polymerase loading. In its absence there is increased 3’ RR polymerase loading and decreased acceptor region transcription and CSR. Thus, ZMYND8 controls CSR by regulating the activity of the 3’ Igh super enhancer.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Rosen, Daniel Benjamin, "The Role of ZMYND8 in Immunoglobulin Class Switch Recombination" (2019). Student Theses and Dissertations. 503.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/503