Transcription-coupled AID deamination damage depends on ELOF1-associated RNA polymerase II

Abstract

In adaptive immunity, transcription-coupled damage (TCD) is introduced into antibody genes by activation-induced cytidine deaminase (AID) to diversify antibody repertoire. However, the coordination between transcription and DNA damage/repair remains elusive. Here, we find that transcription elongation factor 1 (ELOF1) stabilizes paused RNA polymerase II (RNAPII) at transcription barriers, providing a platform for transcription-coupled DNA damage/repair. Using a genetic screen, we discover that ELOF1 is required for AID targeting and that ELOF1 deficiency results in defective antibody class switch recombination and somatic hypermutation in mice. While downstream transcription-coupled repair factors are dispensable for AID damage, ELOF1 mechanistically facilitates both TCD and repair by stabilizing chromatin-bound RNAPII. In ELOF1-deficient cells, paused RNAPII tends to detach from chromatin and fails to recruit factors to induce or repair DNA damage. Our study places ELOF1 at the center of transcription-coupled DNA metabolism processes and suggests a transition of RNAPII from elongation to a DNA damage/repair scaffold.