Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

Summary53BP1 is a DNA damage protein that forms phosphorylated H2AX (γ-H2AX) dependent foci in a 1 Mb region surrounding DNA double-strand breaks (DSBs). In addition, 53BP1 promotes genomic stability by regulating the metabolism of DNA ends. We have compared the joining rates of paired DSBs separated by 1.2 kb to 27 Mb on chromosome 12 in the presence or absence of 53BP1. 53BP1 facilitates joining of intrachromosomal DSBs but only at distances corresponding to γ-H2AX spreading. In contrast, DNA end protection by 53BP1 is distance independent. Furthermore, analysis of 53BP1 mutants shows that chromatin association, oligomerization, and N-terminal ATM phosphorylation are all required for DNA end protection and joining as measured by immunoglobulin class switch recombination. These data elucidate the molecular events that are required for 53BP1 to maintain genomic stability and point to a model wherein 53BP1 and H2AX cooperate to repress resection of DSBs.

► 53BP1 facilitates the joining of DSBs depending on the distance between breaks
► 53BP1 prevents DNA end resection independent of the distance between breaks
► In the absence of H2AX, 53BP1 is chromatin associated but does not block resection
► Multiple functions of 53BP1 are needed for end protection and Ig class switching